Megalo Box is set in Japan in a fictional, futuristic timeline. In the show’s timeline, the class divide in Japan has reached a point where licensed citizens live in the heart of a wealthy city while unlicensed citizens live in the slum outside. In this dystopia, a new sport called Megalo Boxing has become extremely popular. Like boxing, Megalo Boxing involves pitting fighters against each other, but there’s a catch. In Megalo Boxing, fighters wear metal frames and mechanical limbs known as gear to enhance their speed and power. While the sport is a dangerous one, it’s popular across the world, and many compete in it.
In this backdrop, Megalo Box follows a young, promising boxer known as Junk Dog who fights in the underground, illegal fighting circuit. Despite Junk Dog’s talent, his coach – Gansaku Nanbu – fixes fights, and never utilizes Junk Dog’s full potential. However, Junk Dog’s life changes when he almost crashes his motorcycle into Yukiko Shirato, the head of an extremely wealthy group, and picks a fight against Yukiko’s bodyguard, Yūri, who also happens to be the world’s Megalo Boxing champion. Although Yukiko stops the fight, Yūri later seeks out Junk Dog in the illegal fighting circuit, and beats him hands down in one round. With Junk Dog beaten, Yūri challenges him to qualify for the global Megalonia tournament and fight him again.

Qualification to the tournament, which attracts fighters from all around the world, is hardly easy, but Junk Dog takes up the challenge. Backed by the criminal syndicate that fixed his matches, Junk Dog thus takes to professional, licensed Megalo Boxing. However, Junk Dog faces fighters the likes of whom he has never seen before, and he has to give it everything he has if he hopes to enter the final rounds of the tournament. The show traces Junk Dog’s journey as he goes from a lowly, unlicensed boxer to a professional, world-famous one.