Set in Chicago, Illinois, the series follows two people, Mike Biggs, a police officer who wants to shed some pounds, and Molly Flynn, a fourth-grade teacher wanting to embrace her curves, who meet at an Overeaters Anonymous group and become an unlikely pair. However, they also have to deal with the comments, jokes, and criticism from Mike's fast-talking partner Carl McMillan, Molly's slim, drug addicted sister Victoria and nymphomaniac mother Joyce, and Samuel, a Senegalese waiter at the officers' favorite restaurant.
Mike is inspired by their honeymoon trip to Paris to change his life and travel the world, while Molly worries how their family and friends fared at home without them.
Joyce conveniently disappears after a back injury renders Vince practically immobile, and that leaves Mike and Molly to take care of him. Meanwhile, the newlyweds are still laboring over personalized thank-you notes for their wedding presents.
Molly gets upset when she reviews her wedding photos because in every picture Mike's mouth is open or his eyes are closed. Meanwhile, Carl gets jealous when Christina's ex-husband comes back into her life.
Mike and Molly decide the time is right for them to start trying for a baby. Meanwhile, Carl gets upset when he learns that Molly is still spending time with Christina after their breakup.
Mike is forced to set up his mom with his boss, despite his many reservations.
With the house feeling too cramped and crowded, Molly plans a family yard sale. Meanwhile, Mike and the guys take Carl on a fishing trip to help him forget his breakup with Christina.
When Mike gets sick for Thanksgiving, Molly is excited that she doesn’t have to cook – until Vince invites his brother to town for a homemade Thanksgiving meal.
When Mike gets nervous after Molly doesn’t get pregnant following weeks of trying, he turns to Carl and Samuel for advice.
With Molly's encouragement, Mike decides to take a shot at becoming a detective, but the stress of readying for the exam begins to impact their relationship.
Even while portraying Santa, Mike cannot contain his frustrations over Molly's Christmas spending and warns unsuspecting children about the dangers of maxing out credit cards to buy toys. Later, while Molly's family enjoys holiday festivities at home - complete with Christmas carols on Victoria's new karaoke machine - Mike and Molly get roped into spending Christmas Eve at church with Mike's mother and boss.
In an effort to boost their chances of getting pregnant, Molly encourages Mike to join her in giving up caffeine and eating healthier, causing them both to have major withdrawals.
Mike prepares to spoil Molly for her birthday, but his plans go awry after he eats psychedelic gelato made by Victoria’s friend Tom.
Mike puts his construction skills to use turning the basement into a living suite for him and Molly, but he may have gotten in over his head. Meanwhile, Carl asks Samuel if he would be interested in moving in with him.
On Valentine's Day, Mike and Molly play Cupid and prod Harry into asking Victoria out on a date, and to everyone's surprise she accepts. Meanwhile, Carl has a list of reasons why hanging out at the coin laundry on the holiday will help Samuel and him meet single women.
Wannabe-parent Mike takes a crash course in male fertility and heads to a clinic to ensure that he's potent enough to make a mother out of Molly. Meanwhile, Vince starts a job as a door-to-door vacuum-cleaner salesman.
After their verbal brawl at the mall, Mike goes off in a huff, so Molly goes off on a shopping spree.
Carl and Samuel hope for a little luck o' the Irish when it comes to picking up women at their St. Patrick's Day party, while Molly does a little Erin go bragging when she tells Mike about some of her holiday shenanigans.
Molly joins Victoria and her junior-college friends on a spring-fling getaway, while Mike works the Captain for some overtime assignments to earn some extra cash.
Mike’s birthday wish is to have his wife and mother get along, but Molly and Peggy butt heads more than ever as they try to plan his birthday party together. Meanwhile, Samuel and Carl compete for the same woman.
After learning that Joyce gave up her artistic talents when she became a mother, Molly decides that she and Mike need to pursue new hobbies before becoming parents, so they take up roller skating.
Mike goes on a junk food binge to cope with missing Molly while she is out of town for a teacher’s conference. Meanwhile, Carl contemplates leaving Chicago after learning heartbreaking news from James.
Molly is so focused on directing a school recital that she doesn’t realize a fellow teacher is hitting on her. Meanwhile, Vince convinces Mike to join him in an unusual money-making scheme.
Mike and Carl get stuck working at the Renaissance Faire after their boss, Patrick, gets dumped by Mike’s mother. Later, as a tornado descends on Chicago, Mike and Molly each confess important news to each other.
Mike smiles with joy after seeing Molly's advance check after she returned home from an eight week writing shop telling him she's been published.
Molly has writer’s block, and she might lose her big advance if she doesn’t cure it fast
Mike promises Molly he will be home in time for dinner on Christmas Eve--until he and Carl find themselves in the back of a stolen truck; Molly is upset with Vince for trying to alter Christmas traditions.
Mike thinks Carl is out of line when he invites Victoria to go on what is supposed to be a men-only fishing trip.
When Molly starts writing multiple drafts of her book, she starts to irritate Mike and the rest of the family.
Guilt sets in for Mike when he flirts with a rookie cop and she reciprocates.
Samuel contemplates moving back to Africa when he receives a letter from his parents saying they’re struggling financially.
Molly urges Mike to go to the doctor when she learns he hasn’t been in over a decade, on the 100th episode of MIKE & MOLLY.
Molly faces a dilemma when her publisher asks her to make a provocative change to her book.
Mike is forced to arrest Joyce for a DUI after she refuses to take a breathalyzer at a checkpoint.
Mike and Molly are excited to finally have the house to themselves for the whole weekend.
Molly plans a party after hearing that Peggy is suddenly retiring.
Molly’s excited her book is finally out and available for purchase, but worries obsessively that no one will buy it.
Peggy makes Molly do chores in exchange for sharing tantalizing stories from her past for Molly’s second book.
When Mike hits a personal best weight loss goal, he makes the risky decision to indulge in a slice of pie.
Molly is nervous about Mike attending a celebratory party her publisher puts on for her and her mother Peggy.
Molly surprises Peggy by reuniting her with her estranged sister, Rosemary, when they take a road trip to Peggy’s hometown of Mudlick. Also, Vince and Mike experience father-son bonding when they work together to fix the water heater.
When a despondent Kay returns to town, Peggy is thrilled to welcome her back to coexist in her mundane existence. However, Molly is determined to find a way to restore Kay’s joie de vivre. Also, Mike and Carl work crowd control at a rally for public breast feeding
Mike meets his Aunt Rosemary for the first time and is instantly smitten by her warmth and positive attitude – which is the polar opposite of his mother
Molly gets angry at Mike for not listening to her vent about writing with Peggy and they go their separate ways for a day.
After Carl has a near-death experience while on duty, he tells Mike he’s going to propose to Victoria.
When Molly finds herself at a crossroads with her career, she makes a huge decision.
Molly decides writing a crime novel will be her new career, so she goes on a ride-along with Mike to research a book she wants to pen.
Molly has a “mind-blowing” experience when she goes to Victoria’s workplace, a funeral home, to research her novel. Meanwhile, Mike sneaks a peek at Molly’s writing when she’s out.
Budding author Molly meets her literary idol, whose cynical advice is to focus on what she wouldn't want people to know about, while Mike tries to cheer up his down-in-the-dumps mother by having her over for dinner.
Molly believes her suspicious next-door neighbor is up to no good and recruits Joyce to help her spy on him. Meanwhile, the guys get together for a poker game and end up sharing their dreams and aspirations.
Molly needs to adjust her spending habits on shoes if she wants to maintain harmony in her marriage.
Mike decides he needs to live everyday like it’s his last after being shot during a robbery. As a result, he tells Carl it’s time for him to quit the police force.
Molly decides to take a break from writing her novel and accepts a job as a forklift driver at Vince's warehouse, with mixed results.
Molly is determined to get Mike out of his routine and tells him to embrace doing anything they want in life.
Following a dramatic argument with Joyce over money, Mike and Molly move into Mike's childhood room at Peggy's.
Mike asks Carl to replace him as Molly's dance partner at a salsa class, but gets jealous when he realizes they're having way too much fun.
Mike becomes concerned with Molly's state of mind, so he suggests she see a therapist and she begrudgingly agrees.
A suddenly supremely confident Molly doles out advice to friends and family, including Samuel who contemplates doing stand-up comedy, and Harry whom she counsels to stand up to his protective mother.
When Victoria brings around a new boyfriend, the family debates whether she's finally found Mr. Right.
Molly is totally enamored of Peggy's childhood best friend, but her mother-in-law isn't overly fond of sharing.
Molly looks to win some extra cash when she and the girls head to a riverboat casino for the weekend. Meanwhile, Mike and Vince try to enjoy some college basketball when the guys come over to watch TV.
Carl, Mike and Samuel take a road trip to Memphis to meet Carl's mother for the first time.
When Mike's car breaks down, he must decide if he should accept a loan from Carl to fix it.
Mike and Carl arrest Molly’s literary hero, J.C. Small, for a DUI.
Molly wonders if she should tell Mike when she sees Carl coming out of Victoria's room late at night.
After Peggy's bathtub crashes through the ceiling, Mike showers her with requests to go see a doctor.
Molly is ecstatic to be accepted into a prestigious eight-week writer's workshop, but Mike isn't thrilled about having his wife gone for the entire summer.
Mike and Carl go to couples counseling to try to reconcile their partnership. Also, Molly decides to do a promotional radio interview on her own after Peggy decides not to participate.
Molly gives Mike a device that will track his activity in hopes of helping him get healthier and take better care of himself, but Mike has other plans.
Mike blames Molly for Peg's heart attack following a heated argument and now Molly wants to make amends.
Mike becomes hypervigilant after his wallet is stolen from the squad car while taking a nap.
Molly is shocked when Joyce reveals she's leaving the house to Victoria in her will.
Molly's leisure activities between novels become an issue when Mike wants her to be the perfect homemaker.
Mike brings home a stray puppy for the weekend but Molly has difficulty warming up to it.
Mike is upset when Vince bails on finishing a Do-It-Yourself project they started together.
Molly brings home a pregnant former student she discovers is homeless.
When Mike and Molly realize Frannie (Juliette Goglia) doesn't have a plan in place for after the baby is born, Molly decides to help by reuniting her with her estranged sister, Maura (Jessy Hodges).
Mike and Molly need everyone to be on their best behavior when the adoption agency schedules a home visit.
Carl convinces Mike to go with him to see his psychic and Peggy drags Molly to church to pray for something they've all been waiting for.
When Molly suggests that she and Mike write their own wedding vows, he finds it hard to swallow, until Carl provides him with some food for thought and tells him to just pretend he's describing his favorite meal - lasagna.
Peggy goes on vacation and leaves Mike and Molly in charge of her dog, claiming that it's good practice for when they have children.
When Mike and Molly meet with the priest at Peggy's church, Molly's forthright nature winds up costing them their wedding chapel.
Molly's dieting goes into overdrive when her wedding dress doesn't zip during her final fitting.
Two days before their wedding, Mike and Molly arrange their wedding rehearsal which turns into a disaster.
Mike and Molly have to deal with several problems as they make their way to the altar.