Resident Evil: Operation Raccoon City is a third-person shooter and is a spin-off of the long-running Resident Evil series. Unlike the main games in the series, it is less of a survival horror game and more of an action-packed shooter, also prompted by the involvement of Slant Six Games, known for its titles in the militaristic SOCOM series. The game is not part of the series' canon and details a hypothetical scenario set in September 1998 around the same time as Resident Evil 2 and Resident Evil 3: Nemesis. Players control a member of USS, the Delta security team of the Umbrella Corporation nicknamed Wolfpack. It is sent into the Umbrella Raccoon City facility to neutralize Dr. William Birkin who intends to sell the G-Virus that introduces mutations to the American government. Their initial mission is to team up with HUNK, the Alpha Leader to assist with the infiltration and secure the virus.

At the start of each mission the player assembles a team of four characters based on a pool of six with different classes. There is Vector (Recon), Bertha (Medic), Four Eyes (Field Scientist), Beltway (Demolition), Lupo (Assault), and Spectre (Surveillance). Next to a primary and a secondary weapon they all have a different playing style and both passive and active abilities tied to their class. Spectre for instance has a threat scanner to scan nearby enemies, biothermal vision, sonar vision, item detection, and proximity detection (large min-map). Not all of these are available right away, they are unlocked by gaining experience points. The weapons are also selected from a large arsenal with similar unlocks. The game is played from a third-person perspective and combines shooting with cover mechanics. Opponents include infected humans as the T-virus has leaked city-wide as well as mercenaries part of the Umbrella's Biohazard Countermeasure Service (UBCS) who protect Birkin and turn out not to be reliable partners. The player controls a single character as the other team members are controlled by the AI. It is not possible to switch between team members but the game can be played cooperatively with four human players, each controlling a team member.

Next to the shooting, the use of abilities, and various melee attacks, there are two additional mechanics that are used. The first is the use of bioweapons that causes members of the same team or infected to fight each other. Secondly, when the player's character is bitten, he risks getting infected. Health is drained and the character is eventually turned, attacking the team members (while the player is not in control) until an immunisation spray cancels it out.