The Nintendo 64 version of Resident Evil 2 is one of the few games released for the console to have FMVs, overcoming the limited storage space on the cartridge. The PlayStation version with two CD-ROMs of up to 700 MB per disc was faithfully replicated (with unique enhancements) on a 64 MB Nintendo 64 Game Pak. Audio and video assets had to be more aggressively and creatively compressed, using novel techniques that shift the burden more toward the console's high real-time processing power. Over the course of twelve months and with a budget of $1 million, Resident Evil 2 was ported to the console by a team led by nine full-time and one part-time personnel from Angel Studios.

The N64 version of RE2 has unique features such as a difficulty that randomizes items, editing blood color, and new EX Files that reference other games in the Resident Evil series.