Main
Dominic Cooper as Jesse Custer, a preacher from Annville, Texas with a criminal past and a newly discovered superpower to command others to do as he says. Dominic Ruggieri portrays 10-year-old Jesse and Will Kindrachuk portrays teenage Jesse.
Joseph Gilgun as Proinsias Cassidy, a vice-loving vampire from Ireland who joins Jesse and Tulip on their search for God.
Ruth Negga as Tulip O'Hare, Jesse's volatile, hell-raising girlfriend. Ashley Aufderheide portrays 10-year old Tulip.
Negga also played Lucy O'Hare-Custer in the final scene of the series finale.
Lucy Griffiths as Emily Woodrow, a single mother, waitress, church organist, bookkeeper, and Jesse's loyal right hand. (season 1)
W. Earl Brown as Sheriff Hugo Root, Annville's local lawman. (main season 1; guest season 2)
Derek Wilson as Donnie Schenck, Odin Quincannon's right-hand man and Jesse's rival since childhood. (season 1)
Ian Colletti as Eugene "Arseface" Root, Jesse's most faithful parishioner, and Sheriff Root's son, whose face is horribly disfigured due to a botched suicide attempt.
Tom Brooke as Fiore, one of two Adelphi angels tasked with watching the half-demon, half-angelic creature named Genesis. (main season 1; guest seasons 2 and 4)
Anatol Yusef as DeBlanc, one of two Adelphi angels tasked with watching the half-demon, half-angelic creature named Genesis. (season 1)
Graham McTavish as William Munny, the Saint of Killers, a supernatural, unstoppable killing machine summoned from Hell to destroy Jesse.
Pip Torrens as Herr Klaus Helmut Starr, member of the Grail, a powerful, super-secret organization. Starr was briefly introduced in the season 1 episode "The Possibilities", although played by a different actor. (cameo season 1; main seasons 2–4)
Noah Taylor as Adolf Hitler / David Hilter, an inmate in Hell. (seasons 2–4)
Julie Ann Emery as Sarah Featherstone, one of the Grail's best operatives. (seasons 2–4)
Malcolm Barrett as Hoover, one of the Grail's best operatives. (recurring season 2; main season 3)
Colin Cunningham as T.C., a henchman of Marie L'Angelle. This character is briefly introduced via flashback in the second-season finale played by a stand-in. (cameo season 2; main season 3)
Betty Buckley as Marie "Gran'ma" L'Angelle, Jesse Custer's grandmother. This character first appears via flashback in the second-season episode "Backdoors" played by Julie Oliver-Touchstone. (cameo season 2; main season 3)
Mark Harelik as himself / God (guest seasons 1–2; recurring season 3; main season 4)
Tyson Ritter as Humperdoo / The Messiah and Jesus Christ, the last living descendant of Jesus Christ. Christ appears in the fourth season. (guest season 2; recurring season 3; main season 4)