Frankie Paige (PATRICIA ARQUETTE) is a 23-year-old Pittsburgh hairstylist who works in an establishment as likely to pierce or tattoo some part of one's body as give a haircut. Relatively happy with her boyfriend and another good friend and fellow coworker, Donna (NIA LONG), Frankie lives an unremarkable, if not quite mainstream life.
Yet things drastically change after she receives a rosary from her vacationing mother. It turns out her mom unknowingly bought it from a street urchin who himself just stole it from a dead Brazilian priest's coffin. Suddenly Frankie is afflicted by stigmata, crucifixion wounds resembling those suffered by Christ. While hospital workers, who treat her nail-like puncture wounds to the wrists, believe her to be epileptic, a priest who witnesses a later, dramatic crucifixion-like event on a subway car thinks differently and contacts the Vatican.
As such, Cardinal Daniel Houseman (JONATHAN PRYCE) sends Father Andrew Kiernan (GABRIEL BYRNE), a renowned, scientist/priest to investigate the case. Having just returned from the Brazilian church where the suspicious rosary was stolen and a statue bled from its eyes, Kiernan travels to Pittsburgh where he meets Frankie.
Although he immediately dismisses her symptoms due to her being an atheist, her continually developing wounds and subsequent possessed behavior make him think otherwise. His suspicions are further aroused when Houseman abruptly tries to close the case after Frankie writes some mysterious passages in a long lost biblical language.
From that point on, and with the aid of Petrocelli (RADE SERBEDGIA), an older excommunicated priest with an intimate knowledge of what the Church may be frightened of, Kiernan tries to figure out exactly what's happening while also being concerned with saving Frankie's life, particularly since no one has ever received all five of the stigmatic wounds.