The game continues the story depicted in Manhunter: New York. The game begins with the player, piloting an Orb ship in pursuit of the antagonist Phil Cook, crash-landing in San Francisco. Another manhunter on the ground is killed in the crash, so the player assumes his identity. As the gameplay progresses, the player learns of an organized resistance, experiments that have created mutant slaves, and the goal of the malevolent Orbs. The game reaches its climax at the end when the player is on the verge of catching Phil Cook who escapes in an Orb Ship with the player hangs on to the outside, flying off towards London where the third and final game is to take place.
Computer and Video Games (UK) gave the game a score of 61%, criticizing the game's unorthodox mixture of adventure and arcade elements (compared to most other Sierra games of the era). Computer Gaming World gave the game a positive review, calling it, "an excellent followup to the previous game".
^Jeremiah Kauffman. "Manhunter 2: San Francisco Review". Retrieved April 25, 2013. Similar to the first game in the series, Manhunter 2: San Francisco show some potentials in its delivery, but so much more is needed to develop this game to be considered more than just a worthy peculiarity.