After having freed New York from the Orb invasion in Manhunter: New York, you pursue Phil Cook, the mass murderer, to the West Coast. The pursuit ends in San Francisco, where your space ship crashes. With Phil presuming you dead, you take the identity of another manhunter who died as a result of your crash to remain unnoticed and continue taking daily investigation orders from the Orb Alliance. Soon you discover there are several factions in the city resisting Orb rule. There are rat-like mutants, as well as a human Dragon Clan. Both strive and succeed in obtaining the Viewer from the Orbs.
As the Orbs use human slaves to excavate tunnels underneath San Francisco, they need the Viewer to track their slaves as their tracking devices don't work underground. The mutated rat species wants to bribe the Orbs to obtain a cure to turn human again while the Dragon Clan wants to use the viewer to track the slaves in order to free them. Both groups often confront each other, leaving many viciously murdered victims on your path to unravel the mystery of what is going on underground and what the Orbs' true intentions are - the complete destruction of mankind.
Manhunter 2: San Francisco was the third and final collaboration between Sierra and the Murry family and the very last Sierra game to use the AGI engine as new game releases used Sierra's new SCI engine. Although the game hints at a third installment in London and ends with "to be continued" as Phil once again escapes, no other Manhunter game was ever created.
As with the first installment, Manhunter 2 also uses a first-person perspective with occasional third person scenes, often during the arcade sequences throughout the game. They also introduced a difficulty setting for the arcade sequences. Once again, the game does not use a text parser to insert commands - instead the bulk of the game is played by using the arrow and ENTER keys. Evryware took the gore a step further in this game and the plot is more extensive than with the first installment.