- Matt Ryan as John Constantine, an enigmatic and irreverent con man-turned-reluctant supernatural detective who is thrust into the role of defending us against dark forces from beyond.
- Harold Perrineau as Manny, an authoritative angel assigned to watch over Constantine. He communicates with him by temporarily stepping into other people's bodies.
- Charles Halford as Chas Chandler, Constantine’s oldest friend and staunch companion who possesses the ability to be resurrected and healed due to a magical survival spell that John placed on him, imbedding his body with the lives and souls of 48 dead people.
- Angélica Celaya as Zed, a mysterious young woman who has spent the last several years on the run from her father and his cult following, all of who wish to use her powerful psychic abilities for dark purposes.