The remake features all-new graphics and sound and also incorporates gameplay elements from the earlier installments (such as the use of body language and the 180 degree turn). While the overall plot remained mostly unchanged (with the exception of adding the George Trevor diaries), several new areas and rooms were added to the game, including a graveyard and a cabin in the woods. The original live-action FMV segments are replaced by CG versions, and the voice acting was completely re-recorded with new actors. Chris and Jill are still the only two selectable characters. However, if Chris gets poisoned by Yawn, you have to play as Rebecca Chambers to get serum for Chris; there are also some other occasions when you have to play as Rebecca. Most of the puzzles have been changed, and the player's character is now also equipped with a defensive weapon that can be used while being grabbed by the enemy. It is necessary in this game to decapitate or burn zombies to prevent them from regenerating later in the game as the fast and deadly "Crimson Heads." The four crests from the original (sun, moon, wind, and star) used to unlock the door to the courtyard are still present, but instead are used to obtain the Colt Python (magnum) in the graveyard. Another change in the game was the environment: several picture display cases were seen shattered, implied to be either from Albert Wesker himself or Barry Burton under Wesker's influence in order to cover up Wesker's involvement in Umbrella. In the original game, the picture display cases were not shattered.
The game also features many additional modes, secrets, and various endings over the original, as well as restoring the George Trevor sub-plot from the pre-release versions of the original game, while adding his daughter Lisa into the game as a transformed monster (and source of the G-virus). Other additions bring Umbrella researcher William Birkin and Alexia Ashford into the overall plot to make links between the games more clear and numerous.
Shinji Mikami said that the remake is 70% different from the original.