Mega Drive/Genesis version

The Sega Mega Drive version was released in 1991 and was widely popular with comic book fans, helping to establish the success of the 16-bit Mega Drive/Genesis system. Critics noted that the game had superior graphics, sound and faithfully recreated the characters for the video game universe, even allowing the player to take pictures of the major and minor enemies in the video game to sell at the Daily Bugle to buy more web fluid. The additional ultra-hard challenge was a fight with Venom at the end of each round, before reaching the actual boss. In addition to Venom, there are also many other popular Spider-Man villains that player would have to fight, such as Doctor Octopus, Lizard, Electro, Sandman and Hobgoblin.

According to developer Randel B. Reiss, this version was a huge commercial success: two thirds of all Mega Drive owners at the time also bought the game, and single-handedly convinced Marvel Comics not to cancel the licensing deal they had with Sega.

Master System / Game Gear version

The 8-bit Sega Master System version is noted as one of the last Master System games sold in America. It had the same basic format and storyline as the 16-bit version, with redesigned levels, cutscenes (that included a cameo from Doctor Strange) and even on the easiest setting was seen as being difficult to complete. In this version Mary Jane wouldn't be kidnapped but still appear at the end of the game if players attain the best ending.

A nearly identical port was also released for the Sega Game Gear portable system.

Mega-CD/Sega CD version

The 16-bit Mega-CD/Sega CD version (1993) made several improvements to game to take advantage of extra memory capabilities of the CD-ROM system. Animated scenes, with voice actors, were added to move the story along and to show what happened when the player died. The game also added two new levels, extra combat moves, the ability to collect reproductions of famous Spider-Man comic books issues, and an original musical score by Spencer Nilsen and the Mr. Big rock band. The game also was more non-linear as the player could venture to various locations throughout the city (including a local television station). However, the ability to take pictures during the game in order to earn money for web fluid was taken out of this version. The game also added two new levels (Mysterio's Funhouse and the Vulture in the subway). In addition, before battling the Kingpin, the player must first defeat Bullseye and Typhoid Mary. The game had three different difficulty levels (easy, normal and nightmare) and a contest was held (details were provided in the instructions manual along with a sheet to mail in) to see who could successfully complete the game in the ultra-hard nightmare mode and collect all 21 comic book covers.

The Mega-CD version featured some alternate cutscenes depending on the Kingpin boss level. If the player beats Kingpin, but not in time to save Mary Jane from falling into the acid pit, the police would arrest Kingpin and Spider-Man would vow to avenge Mary Jane. If the player fails to defeat Kingpin (or his bodyguards), Spider-Man and Mary Jane would both be dropped into the acid pit. The Mega Drive version is similar, only Kingpin will escape once Mary Jane is killed, leaving a heartbroken Spider-Man on his knees.

In the Master System version, Mary Jane doesn't get kidnapped. If the player loses the final battle, though, Kingpin will get away.