What made Ray McCall put down his revolver and become a reverend in the town of Hope? A question Call of Juarez never answered. The successor, Call of Juarez: Bound in Blood tells the story of what happened 20 years ago that dramatically changed the life of a fearsome gunslinger. The story begins right during the War of Secession with Ray and his brother Thomas as soldiers in the confederation. But soon they realize that their family at the farm in Georgia is in danger and they leave the army as deserters only to arrive home too late. Only their youngest brother, William, survived the attack. While he tries to give his brothers strength through faith, Ray goes on a rampage for revenge - pulling Thomas right with him down a dark path that in the end can only lead to the inevitable.

At the beginning of a level, the player normally has the option to choose between playing either Ray or Thomas. Only in a few missions the game decides this. Choosing with which character to fight his way in first-person-shooter style through the levels greatly influences the gameplay. While Ray shoots first and asks questions later, he can neither climb over obstacles nor use bows or throwing knives for stealth kills. On the other hand Thomas could not even kick in a door if his life depended on it. So most of the time the two need to work together. Sometimes though the characters split up and the mission progresses differently for each one of them. In addition at certain points in the game the two use their coop concentration mode together, allowing them to simultaneously slow down time and use their two different special attacks to take down large groups of enemies. While Ray has to aim during concentration mode to unleash hell on his enemies afterwards, Thomas's cross-hair automatically jumps from enemy to enemy but requires the player to pull the trigger manually each time. Similar to the duels, in which the player needs to draw his gun in one move before he can fire, this is done by performing a virtual backwards pull with the mouse or the analog stick. To limit the access to concentration mode, its "power" needs to replenished by killing six enemies and only holds for a certain amount of time if not used before it vanishes.

Besides the story campaign, the game also features a class-based multiplayer mode for up to 12 players. While no coop-mode is available, the players can shoot each other in Deathmatch, Team Deathmatch and Wanted. In Wanted one player takes on the role of a wanted criminal and needs to be taken down. The player that manages to put him to rest then automatically becomes the criminal himself. Manhunt builds on that premise by putting a whole team on the hunt for the wanted criminal for 60 seconds which himself is defended by a complete team. The last mode, Historical Events, pits two teams against each other where one team needs to fulfill objectives during a time limit (like blowing up a weapons cache) with the other team tries to stop them.