Translation errors
Further notes

Unlike subsequent Resident Evil games, the first game had live-action openings and endings. The acting and dialogue in these scenes are often mocked (as is the general dialogue in the series). But some argue that the unrefined, campy and poor execution perfectly fits the mood of a B-grade horror movie, although the majority of the series' fans continue to mock the opening, as it completely offsets the otherwise horror-driven mood of the game. The opening footage in the western releases was significantly recut to exclude most of the gore, (and Chris lighting a cigarette) using alternate footage. Capcom was supposed to include the unadulterated version of the intro in later revisions, but only the PC Version as well as the German and French PAL PlayStation Director's Cuts contain the original FMV.

The gameplay environment consists of polygonal 3D characters placed over pre-rendered 2D backgrounds. As such, the game relies on pre-determined camera angles for view of the action instead of a real-time camera like most games. As a result, the game uses a "tank-like" control scheme where the character controls in a first person manner. Instead of moving the character in the direction the player is pushing, the character moves forwards by pressing up and backwards by pressing down and turns the character on the spot by pushing left or right. Many Resident Evil detractors have criticized this control scheme, claiming it unsuitable for a third-person action game. On the other hand, many fans have defended it, arguing that it added to the feeling of death and defeat and that a conventional third person control scheme would be infeasible considering the various camera angles.

The player fights against enemies by arming their character with a weapon. The player draws their weapon by holding down the "Weapon Draw" button (usually a shoulder button, such as the R1 button on PlayStation) and fires it by pressing "Fire" (X button on PlayStation). In the attack stance, the player character remains static in one place and can turn their character and/or tilt their weapon up or down. Initially, the only weapons available to the player are a combat knife and a Beretta 92FS. Later in the game, more weapons become accessible to the player, such as the Remington M870 and the Colt Python. Ammunition for firearms is limited and it is often recommended that the players save their strongest weapons for boss battles.

The player must survive by fighting against the various monsters that populate the mansion. The most common enemies in the game are Zombies, which are slow-moving and easy to outrun, but harder to avoid in tight corners. During later sections of the game, the player must also fight against zombie dogs (known as "Cerberus'"), Hunters, Chimeras and Web Spinners, as well as small enemies such as crows, wasps and adders. The latter three are small and fast, and the player should be careful to conserve ammunition when dealing with these. The player must also fight against bosses such as a giant snake (Yawn), a mutated plant (Plant 42), a giant spider (Black Tiger), a giant shark (Neptune), and the Tyrant (T-002 Type).

Health is restored by using First Aid Sprays or healing herbs. Of the two, healing Herbs are more common and restore a portion of the player's health, while first-aid sprays are scarcer, but will restore the player's health completely. There are three types of healing herbs available: the green herb (for restoring health), the blue Herb (which cures poison) and the red herb (which can't be used by itself, but will triple the healing power of a green herb when mixed with one). The herbs can be mixed and used in six different combinations (see topic Herbs for reference).

The player must navigate through the mansion by picking up various keys and items which are pivotal to the game's progress, while solving puzzles along the way. The player has a limited capacity for carrying items, thus enforcing the need to carry only essential items while still having space for new items. As such, storage boxes are available for the player to store any item for later use.

The player can only save their progress by going to a typewriter and using ink ribbons to save the game. Ink ribbons are available in limited quantity, forcing the player to seriously consider whether they have made enough progress to justify saving the game. This saving method has also been criticized by many, but designer Shinji Mikami defended it, arguing that it increases the tension in the game.

There are also various documents available to the player within the mansion which either serve to provide the solutions to certain puzzles, or simply to further divulge the plot.

The game gives the player control of S.T.A.R.S. Alpha team members Chris Redfield or Jill Valentine as they search for a way out and attempt to locate the S.T.A.R.S. Bravo team. The characters play out similar scenarios but they have different skills. Chris is assisted by Bravo Team medic Rebecca Chambers (who becomes playable in certain portions of his scenario), while Jill gets help from fellow Alpha team member Barry Burton. Jill's quest is easier because she has a higher item-carrying capacity (eight compared to Chris' six), can pick simple locks with her lockpick (Chris has to find small keys (called old keys in the REmake) to unlock the locks concerned) and has a comparatively stronger teammate. She also has access to a grenade launcher (Chris has very limited access to a flamethrower) and can complete certain puzzles by herself, while Chris needs Rebecca's help in certain areas. Chris' limitations make his quest arguably more difficult but he has more stamina than Jill, therefore being able to sustain greater damage and run faster.