In single mode the player can choose to undertake the game's quest against the Cabal as one of the four Chosen. However only when playing as Caleb the in-game cinematics are shown and the story developed (playing as Caleb will therefore be considered as the standard choice throughout this article). Blood II gameplay is influenced by the character choice at the game start-up because every Chosen has different weapons marksmanship levels and different amounts of maximum hit points and armor level. For instance, Gabriella can deal out the maximum damage when using firearms, but she is not skilled in the usage of magical items. She also has the strongest armor level available. Conversely Ishmael and Ophelia are more dangerous when using magical weapons, such as the Voodoo Doll or the Life Leech. Caleb is the most balanced character being able to use with good efficiency both firearms and magical means.
The game is divided in chapters: each chapter can be reached by the player only completing the previous one. During the first chapter Gideon appears on a Cultist filled underground train, taunting Caleb and starting the chase that will take Caleb across the city, into a museum, through the steam tunnels, to CabalCo's Center for Disease Management, an airship, then again across the city and to an old cathedral in ruins for the showdown with the first boss. During this chapter Caleb is reunited with Gabriella, who used to be Gabriel in the first game. As she witnesses Caleb's perplexity at her change the only answer given by Gabriella is: "It's a long story." The second chapter starts again on an underground train, filled with more dangerous enemies leading back into the city. Caleb will storm across entire districts and wreak havoc in a CabalCo Meat Packing plant until he reaches some catacombs and the second boss. During his wandering Caleb will also meet Ishmael who informs him that only by using the Tchernobog powers the dimensional rifts can be closed. Back on an underground train for the third chapter (with even more deadly foes), Caleb travels to the top CabalCo facilities such as their Research & Development building and the company HQ for a first fight with Gideon. When Gideon flees using a dimensional rift, Caleb can finally meet with Ophelia, but any celebration for their coming back together has to be postponed, since Caleb decides to enter a rift himself to finally get rid of Gideon and to repair the fabric of space and time.
Blood II multiplayer features some of the common game modes seen in the most recent first-person-shooters. Bloodbath is the equivalent of deathmatch and is the most widely played multiplayer mode. Each player can choose one of the Chosen to control during gameplay. Every character starts equipped with the weapons he excels with, so this means Gabriella will have all kind of firearms in her arsenal, while Ishmael will carry mostly magical weapons.