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 attends his high school's football game, which turns into an extraordinary, explosive sporting event.
Milo, Melissa, and Zack try to protect an egg for a science experiment.
Sara wants to see The Doctor Zone Files movie with Milo, but worries about potential problems.
Milo and the gang spend the entire day chasing after his doctor's note.
Melissa and Zack organize a surprise birthday party for Milo, which can be a risky endeavor.
Milo, Melissa, and Zack go with their classmate Amanda to an opera concert for extra school credit.
It's career day and Milo is having a hard time deciding what his career should be. He tries to decide while visiting the water works, fire department, and hospital. But of course, everything goes wrong. Meanwhile, Dakota and Cavendish try and make sure a shipment truck full of pistachios make it to the pistachio warehouse.
Milo and his friends visit a dude ranch. While horse back riding, they meet a girl named Jackie who joins their posse, and Zack is smitten with love. But, Jackie leads them into more danger than usual. Meanwhile, Sara is going crazy because the ranch reminds her of scenes from The Doctor Zone Files, and invites other fans to join in the geek fest.
Milo accidentally vacations with the wrong family.
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.
Milo, Zack and Melissa go to school after sunset to retrieve Melissa's math book. Unfortunately, she leaves the spare key inside the locked classroom, so the three go on a "quest" in search of the mysterious janitor, otherwise known as the "key-keeper".
When Melissa’s dad drives her and Milo into town on a decommissioned old fire engine, chaos ensues.
Milo and Melissa finally tell Zack the story of the infamous Llama Incident.
Milo learns that his favorite actor is supposed to be currently shooting a film nearby in town and decides to travel to the set and get his autograph.
Elliot Decker is put in charge as the school's head safety monitor.
Milo, Zack and Melissa set out in search of a missing robot that previously escaped.
Milo begins to sleepwalk through some nearby woods. Meanwhile, Cavendish and Dakota have a "ditch day" from pistachio duties after the ordeal from the evil pistachio creatures.
The students embark on a special trip while using the school's yacht.
During a Back to School Night event, the parents suddenly become children, thanks to Dakota's stolen time device.
One morning, Elliot wakes up to discover that Milo has been erased. At first, he is naturally overjoyed, but soon becomes bored.
Milo participates in a race and relies on Melissa and Zack to throw him reinforcements from his backpack to finish it. Meanwhile, Cavendish and Dakota, while attempting to stop the re-assigned Brick and Savannah from saving the pistachios, find themselves in the Old West and meeting Milo's great-great grandfather, Sheriff Murphy.
Sara contemplates whether or not she's on a date with Neal from the comic book store. Milo, Zack, Melissa and Mr. Murphy go to the skiing slope, but the former three's toboggan goes out of control.
Cavendish keeps dying and Dakota repeatedly makes time paradox duplicate versions of himself to save him. Milo, Zack, and Melissa go to see Hamosaur 2, but Milo can't find his shoes.
Milo, Cavendish, and Dakota travel to 1965 to help Orton Mahlson create The Doctor Zone Files. Unfortunately, they find that Derek, the son of King Pistashion, has somehow survived and has body snatched pretty much everyone, even in the present. In a cliffhanger, it turns out their sole hope lies in a particularly incompetent pharmacist.
Milo builds his own haunted house out of a decommissioned old truck and invites his friends to the fright fest, but Zack is not too amused because he's grown out of being scared on halloween, but thanks to Murphy's Law and the truck going on a wild ride throughout town, Zack slowly changes his mind. Meanwhile Dakota and Cavendish take in on the halloween fun while also investigating the mystery of the last halloween, which not surprisingly happens because of them, actually Dakota, and a wayward time grenade.