Mega Man 10 takes place in the 21st century, in which a disease begins infecting and disabling robots, hampering daily life for humans.

An illness known as "Roboenza" suddenly begins infecting robots all over the world, causing them to malfunction and hamper human life.

[8] The villain Dr. Albert Wily comes to Mega Man and Dr. Thomas Light, claiming that he was building a machine that was capable of making medicine to cure the disease before one of the infected robots stole it.

The situation worsens once Dr. Wily appears on television and reveals that he created the virus, and only developed a cure so he could bribe all the infected robots into coming to work for him.

[10] Just as Dr. Light initially forbids Mega Man to go after Dr. Wily, Roll -- still also infected by Roboenza -- gets out of bed and gives her brother her medicinal capsule, saying that she had been saving it in case "a really sick robot was brought in."

However, she continually tells him that swallowing it will still render her unable to fight Dr. Wily, because Dr. Light created and programmed her with no built-in Variable Weapon System of her own for a long time.

[13][14][15] An in-game shop allows the player to use screws picked up in the stages to buy extra lives, energy tanks for refilling health and weapon power, and other useful items.

Mega Man 10 includes several difficulty modes, which alters level layouts, enemy AI, and damage done to the player character.

He also has a dash maneuver for longer jumps and the ability to summon his wolf Treble to allow him to fly, provide him with power-ups, and save him from bottomless pits.

[19] Producer Keiji Inafune, who was involved with nearly the entire franchise, stated that choosing such a "retro" style for Mega Man 9 was a huge, overwhelming success for the developers.

The team decided that for the tenth installment, they should listen to both old-school gamers and former Mega Man players who have not recently played video games.

Various former composers in past installments in the main Mega Man series, returned to write single Robot Master themes for Mega Man 10, which included Manami Matsumae, Yasuaki Fujita, Minae Fujii, Mari Yamaguchi, Yuko Takehara, Makoto Tomozawa, Akari Kaida and Shusaku Uchiyama.

[25] Christian Svensson, Capcom's Senior Vice President of strategic planning and business development, stated that the company was pleased with the sales of Mega Man 10.

[26][27][28] IGN's Colin Moriarty praised its gameplay, challenge mode, and the addition of Proto Man as a playable character, which he said adds more depth to the game.

[14] 1UP.com's Jeremy Parish gave the game a B grade, calling it fun, but stating that it fails to capitalize its predecessor in a meaningful way, claiming overly similar gameplay, uninspiring level design, and forgettable music.

Time travel stories in issues 20 and 55 involved Mega Man being shunted forward to the events of the game and Dr. Light experiencing a vision of them but not understanding the cause of so many Robot Masters going haywire.