The game's story takes place after the third defeat and supposed death of Dr. Wily in Mega Man 3, and features the Earth coming under threat from a mysterious scientist named Dr. Cossack and his eight "Robot Masters".

One year after the events of Mega Man 3, a mysterious Russian scientist named Dr. Cossack unleashes an army of robots with the intention of world domination, much like Dr. Wily before him.

Dr. Light calls upon his own greatest creation, the hero Mega Man, to go after Cossack's Robot Masters, who have seized control of eight cities.

Mega Man escapes as the fortress begins to self-destruct, and rides home on the top of a passing train, where he is greeted by Roll and Rush.

[14] The hero's dog Rush makes a return from Mega Man 3 with the ability to transform into "Coil", "Jet", and "Marine" modes for navigating different environments.

Eddie, who went on to appear in later Mega Man games, provides the player with a random item (such as health, ammunition, or an E-Tank) at designated points in some of the levels.

Eddie was designed as a supporting character that "would behave like a lottery", either pleasantly surprising or disappointing the player with the item he gives Mega Man.

[2] "We knew adding a two-level or three-level charge would change the whole flavor of the game in some respects, and we were very mindful of that," Inafune explained.

"Mega Man 4 continues the tradition — crazed robot baddies, good character graphics, great background art and warped, mechanical music," the reviewer said.

[24] Lucas M. Thomas of IGN stated that, as a stand-alone title, the game is one of the best experiences available from the NES library, although not when compared to its superior predecessors.

[20] Numerous video game journalists and enthusiasts including Thomas, Craig Skistimas of ScrewAttack, GameSpot editors Christian Nutt and Justin Speer, and 1UP.com's Jeremy Parish, refer to the fourth installment as a turning point for the quality of titles in the Mega Man series.

[14][20][25][26][27] Nutt and Speer admitted that the series was beginning to deteriorate with this game, likely due to the growing reputation of the more powerful Super Nintendo Entertainment System at the time of its release.

[26] Parrish proclaimed, "Here's where the series starts to go off the rails a bit -- the Dr. Wily fake out was silly, the music was terrible, the bosses and weapons were uninspired, and the ability to charge up the Mega Buster is often cited as a game-breaking innovation.

[28] A port of the Complete Works edition was released on the PlayStation 2 and GameCube in 2004 and the Xbox in 2005, as part of the North American-exclusive Mega Man Anniversary Collection.

[35] Created by developer PureSabe, the ROM hack has received positive reception for its extreme difficulty and creative transformation of the original game's source material.