The entire group gets captured again and sent to DeVitt's mines as slaves. Alone, he proceeds onto a docked freight ship, where he and Frank duel. At Hector's mention of James Cooper's fate, John snaps and shoots Hector in the arm. Having sneaked past the roadblocks and guards, Cooper asserts that he wants to face Frank alone, to which Kate and Hector object. This act puts Frank on alert, and he locks down the city.
Once they rescue Wayne, the group sets fire to the old riverboat that functions as a headquarters for Frank's people. Frank's gang have imprisoned many people out in the Louisiana wetlands, to be shipped off to work in DeVitt's mines. Together, they set out to find her partner, Marshall Wayne, who disappeared while investigating DeVitt.
A Voodoo practitioner called Isabelle Moreau rescues them. The group eventually gets captured on their way to New Orleans, where Frank, who is working for DeVitt, is located. The defense is successful, but Kate's uncle Ian perishes in the battle. The newly met pair promptly escape the mansion and head for the O'Hara ranch to defend it from the attacking DeVitt company men. In the escalating altercation, O'Hara shoots the mayor as John Cooper walks in, seeking Frank. In the meantime, the mayor's prospective bride, Kate O'Hara, finds out that her betrothed has sold her family's ranch to DeVitt. Once in Flagstone, Cooper learns from his friend Hector Mendoza that Frank is at the mansion of the soon-to-be-married local mayor. Along the way, Cooper meets Doctor McCoy, who was hired by the DeVitt Company, a wealthy corporation, to defend the train Cooper was taking on his way to the town of Flagstone. The story follows bounty hunter John Cooper as he pursues Frank, a notorious bandit leader responsible for killing John's father, James Cooper. In addition to John Cooper, the game also includes Hector Mendoza, Doc McCoy, Isabelle Moreau, and Kate O'Hara as playable characters. The game is set in the Wild West in the 1870s and features various locations including Colorado, Louisiana and Mexico. The story is a prequel to Desperados: Wanted Dead or Alive, the first game in the series, and explores the origin of the series' protagonist John Cooper.
When the player exits showdown mode, the characters will execute the commands issued by the player simultaneously. In showdown mode, players can issue commands to each of the character in the party. Players can also play the game as an action game and utilize the showdown mode to temporarily stop the game, allowing players to coordinate and chain up the actions of the player's squad. The cones of vision of all enemies are displayed, allowing players to navigate the map without alerting them. Bodies of incapacitated enemies need to be hidden or else other enemies patrolling the area will discover them and trigger an alarm that calls for reinforcement. It is possible for players to complete missions without killing anyone by knocking out and tying up enemies. Players can play the game as a stealth game, in which they can assassinate enemies silently or disguise kills as accidental deaths. The game features five playable characters, with each having access to unique weapons and abilities. Desperados III is a real-time tactics stealth video game.