The film centers on the character of Rayne (BloodRayne), an unholy breed of human and vampire known as a dhampir. Dhampir are unaffected by crucifixes and do not thirst for human blood, but maintain a vampire weakness to holy water. She is the daughter of the Vampire King, Kagan, who has gathered an army of thralls, both vampire and human, in order to annihilate the human race. She was conceived when Kagan raped her mother, and she later witnessed him killing her when she rejected his advances.
Rayne, the half-human/half-vampire warrior, ventures to America's 1880's Wild West to stop the now vampire Billy the Kid and his posse of vampire cowboys.
Rayne (BloodRayne) fights against the Nazis in Europe during World War II with the French French Resistance, encountering Ekart Brand, a Nazi leader whose goal is to inject Adolf Hitler with Rayne's blood in an attempt to transform him into an all powerful dhampir and attain immortality.