Milo Murphy is the personification of Murphy’s Law where anything that can go wrong will go wrong. Suffering from Extreme Hereditary Murphy’s Law condition (EHML), Milo always looks to make the best of the cards he’s been dealt and his endless optimism and enthusiasm can turn any catastrophe into a wild adventure. Together, he and his friends will learn that it’s all about a positive attitude and not to sweat the big stuff… and it’s all big stuff.
Zack Underwood, a new kid in town, meets Milo Murphy, the unluckiest kid in town. Because of Milo's misfortune, he and Zack both miss the bus for school, so Milo shows Zack a "shortcut" to school, while attempting to avoid wolves, bees, fire, and even an alien abduction. Meanwhile, Melissa Chase, a friend of Milo's, collects lunches as wagers from other students on whether or not Milo and Zack will make it to school before the bell rings.
Milo, Zack, and Melissa's subway car gets derailed on their way to a field trip to the museum. While trying to find their way to the museum, they encounter a society of construction workers who have been underground for a long time.
Milo is allowed to attend his first school football game since his school team, The Geckos, will lose anyway. After a few fiascoes thanks to Milo cheering his team on, he realizes that if he cheers for the opposing team, The Tigers, his school might have a chance of winning.
Milo, Melissa and Zack try to protect an egg for a science experiment.
Milo and his sister, Sara, who are huge fans of the science-fiction television series The Doctor Zone Files, take "newbies" Zack and Melissa along with them to see the new Doctor Zone movie. However, Sara is hardly taking any chances with the effects of Murphy's Law.
Milo and Zack try to help Melissa overcome her secret fear of roller coasters.
Milo and Melissa share their most embarrassing stories, but Zack refuses.
The gang participates in a school event that combines the Academic Decathlon and the Athletic Decathlon.
Milo's science class deals with a bored substitute. Meanwhile, Cavendish and Dakota hide in the classroom's closet to hide a substance that will help pistachios grow.
Milo and Zack go fishing with their dads. Meanwhile, when their phone battery dies, Cavendish and Dakota interfere with Brick and Savannah's time travel mission.
At a donation drive, Milo accidentally gives away his mother's precious vintage T-shirts. Cavendish and Dakota are assigned to protect the pistachios at the zoo.
Amanda does everything she can to make sure the school dance goes off without a hitch. Cavendish and Dakota go to the dance to attempt to prove without a doubt that Milo is another agent attempting to thwart their plans. Mort mistakes Cavendish and Dakota for vampire hunters.
Milo, Melissa, Zack, and Mort's band enters the battle of the bands. Zack discovers his old boy band is competing in the battle.