There are things in the world that humanity should not know about, and things it must be protected from. It is these things that the Brimstone Society hunts, and their newest agent for the cause is the half-vampire codenamed BloodRayne. Her mission will take her from clearing out the walking dead and man-sized insects in the swamps of Louisiana to hunting down members of the secretive Gegengheist Gruppe branch of the Nazi military around the world, as well as the monsters they unwittingly awakened.

Rayne's primary weapons against both monsters and men are the blades attached to her arms, and as the game progresses she will gain additional attacks to string together. Rayne can also hold many weapons, such as pistols, shotguns, and submachine guns, at once, but she is not overly attached to them and will discard any weapon that runs dry. Her enhanced vampiric strength even allows her to rip up mounted gun emplacements and fire them from the hip. Another vampiric strength is her ability to drain the blood out of any human she can grab in order to restore her health. By killing enemies Rayne's rage meter will fill, eventually allowing her to enter Blood Rage, slowing the world around her and gaining new combo attacks that can dismember or totally cut in half weaker opponents. Rayne's ability to perceive the world will grow as the game progresses as well, allowing her to see living things through walls, zoom in on distant targets, and speed up her perception that everything, herself included, appears to slow down.