In the year 2010, Rainbow operatives Logan Keller (), Gabriel Nowak (Thomas Michael) and Kan Akahashi () are on a mission in a border town, assisted by intelligence officer Joanna Torres () and pilot Brody Lukin (). Their objective is to arrest Irena Morales (Amanda Martinez), a terrorist ringleader. As the team reaches its landing zone in a helicopter, Logan down first but is separated from his group.
Logan fights his way through the terrorist-infested streets and meets up with Gabriel and Kan at an old Spanish church. After infiltrating a train yard and freeing a group of hostages, Rainbow eventually makes their way to a mine where Irena is hiding. However, after a surprise attack, Irena escapes and Gabriel and Kan are captured by terrorists.
Alone and armed only with his sidearm, Logan fights his way through an abandoned factory, eventually escaping by helicopter. He is then instructed to handle a related crisis in . He is dropped outside the Calypso Casino and links up with his new team: Michael Walters (), a British demolitions expert, and Jung Park (), a Korean electronics expert. The team clears out the casino and saves a group of hostages. They also rescue a equipment researcher, who reveals that a second researcher has been captured.
Rainbow is then taken to the Red Lotus casino in order to rescue a kidnapped reporter. The reporter informs them that the terrorists are using a news van as a communications hub. Logan's team destroys the hub, then flies out to rescue the kidnapped equipment researcher. Rainbow is dropped on the Vertigo Spire, a luxury hotel along the likes of the . The team finds and rescues the missing researcher, who informs the team about a micro-pulse grenade that was placed in the Vertigo. Michael disarms the grenade, and Rainbow is then extracted to locate Gabriel and Kan.
- Rainbow Six Vegas changes the series with multiple new features, such as a new health system where the player regenerates health while not taking fire (the player may sometimes be killed instantly, without a chance to regenerate health; this usually happens from grenades, as well as taking close-range fire from very powerful equipment, particularly to the head). The player's vision is greatly impaired while damaged, similar to the health system in
- Furthermore, a view has been included for moments where players can blind-fire around corners to lay down suppression or covering fire. Other changes include a larger enemy presence and much tougher artificial intelligence
- a shift in focus to where kills will be much harder to obtain, a reincarnated aiming system similar to the aiming system of the old Rainbow Six games and a based command system for the player's squad and sections of gameplay where the player will scale buildings and cause environmental damage
- The player can also give voice commands using the Xbox 360 and PlayStation 3 headset, but teammates are no longer audible through the headset