Lt. Simon "Ghost" Riley is first seen in Takedown talking to Captain MacTavish via radio while they search for Alejandro Rojas's assistant After Soap and Roach begin pursuing the assistant, Ghost meets up with them at the Hotel Rio and joins the chase. Once the assistant is taken down by Roach, he is seen with MacTavish preparing to interrogate him. Ghost is then heard via radio for the rest of the mission as he attempts to pursue Rojas through the Favela. After the capture of Rojas, Ghost is heard requesting extraction from Command but to no avail.

Ghost appears in the mission The Hornet's Nest where Task Force 141 attempts to escape Rio de Janiero while being pursued by the Brazilian Militia. He manages to escape with Captain MacTavish and Roach aboard Nikolai's helicopter. He then takes part in the infiltration of the Russian oil rig, which is being used as a makeshift SAM (Surface-to-Air-Missile) site in The Only Easy Day...Was Yesterday. After clearing the oil rig, Ghost takes part in the operation to rescue Prisoner 627 from a Russian gulag. He takes control of the gulag's security systems and guides Soap and Roach to the prisoner.

Ghost, lying in a ditch after being shot by Shepherd in Loose Ends.Ghost does not reappear until Contingency where he helps Captain Price infiltrate a Russian submarine base along with other Task Force 141 members. However, he is shocked after Price launches an ICBM at Washington D.C. where the Russian-American war rages on. Ghost's final appearance is in Loose Ends where he leads a strike-team to search for Vladimir Makarov at his safehouse on the Georgian-Russian border. However, Makarov is nowhere to be seen but the safehouse is rich with intel. Ghost along with Roach, Ozone and Scarecrow with sniper support from Archer and Toad, protect the DSM while it downloads information regarding Makarov's operations. As the team head to the LZ set up by Shepherd, Ozone and Scarecrow are killed by enemy mortars and Roach is injured. Ghost manages to get Roach to the LZ but Roach is betrayed by Shepherd who shoots Ghost, before he could level his ACR, in the chest at point-blank range with a .44 Magnum. Ghost is last seen being thrown into a ditch along with Roach. Although the player only sees Roach being covered in gasoline and set on fire, Ghost is undoubtedly lit on fire along with him (the soldiers would not have left unless they were sure they both were dead)