In Operation Flashpoint: Red River, players assume control of Outlaw-2-Bravo, a United States Marine Corps fireteam during a fictional conflict in Tajikistan in 2013. A terrorist group known as the ETIM launches mortar attacks on a US FOB in Afghanistan, prompting the United States to launch operation Enduring Shield, having the Marine Corps invade west Tajikistan and wipe out the Insurgent threat. Later during the conflict, the People's Liberation Army of neighboring China intervenes and attacks American and terrorist forces alike. The majority of the game's events picture the desperate struggle of the Marine Corps against the overwhelming Chinese.

The gameplay is pretty much what one can expect from an Operation Flashpoint game. The player are able to choose between four classes of Marines to play as, rifleman, grenadier, scout and automatic rifleman, each with their own weapons and abilities. He gains experience during gameplay, which can be used to unlock guns, attachments and perks. The enemies are able to kill the player with a single shot, depending on the hit zone. Using the squad members at the player's disposal the right way is vital for success. The player also has the choice of playing the campaign cooperatively.