Milo Murphy - He is the protagonist of Milo Murphy's Law, voiced by "Weird Al" Yankovic. He has a reputation for having extreme misfortune, but he is always optimistic and finds ways to overcome it. He carries a seemingly bottemless backpack with him that always seems to have what he needs for any given situation. It was given to him by his old babysitter, Veronica, whom was the only one able to handle Murphy's Law. Milo is the youngest of the three.
Melissa Chase - She is voiced by Sabrina Carpenter, a long-time friend of Milo's who likes to hang out with him despite his bad luck. Her father is the local fire chief. She has had a secret fear of rollercoasters since one nearly fell on her. (The rollercoaster fell on a science project was Phineas and Ferb's first rollercoster.)
Zack Underwood - Voiced by Mekai Curtis. He is the new kid in Danville who becomes friends with Milo and Melissa and sticks by Milo even though he is a jinx. He is on this school's football team. He was once the lead singer of a boy band called The Lumberzacks. He also has a fear of fish and says that they are scarier when they are in bags. His mother is a doctor whom handles bloody matters. Zack is the oldest of the three.