It's 1979 and Frank Shore (ED HARRIS) is a postulator for the Catholic Church, although the fact that this middle-aged priest continually questions his own faith makes some wonder if he's the right choice for investigating reports of religious miracles.
Nonetheless, and due to a history of successfully debunking enough such occurrences that Frank's earned the nickname, "The Miracle Killer," Bishop Cahill (CHARLES HAID) assigns him to investigate reported miracles at St. Stanislaus in Chicago. There, Father Paul Panak (KEN JAMES) has reported various inexplicable occurrences, including a statue of the Virgin Mary that weeps blood, ever since the death several years earlier of a charitable, immigrant laywoman, Helen O'Regan (BARBARA SUKOWA).
As such, Frank must not only investigate the supernatural occurrences, but also determine whether Helen should be considered for sainthood in the Catholic Church. Thus, he begins researching the various miracles, including one involving Maria Witkowski (CATERINA SCORSONE), a prostitute and addict who was miraculously cured of a terrible disease when she was a young girl. He also meets Helen's adult daughter, Roxanna (ANNE HECHE), a bitter, nonreligious young woman who still harbors ill feelings toward her mother for leaving her while a teen to work for the Church, and thinks consideration of her as a saint is pathetic.
With the aide of Brother Gregory (JAMES GALLANDERS) who serves as his assistant detective of sorts, Frank continues his difficult quest all while discussing his own faith-related problems with fellow priest John Leone (MICHAEL RISPOLI). Despite their differences and varying beliefs and the potential for such a romance clouding his judgment, Frank also finds himself falling for Roxanna.
Eventually, however, he must face a Vatican-appointed committee led by Cardinal Sarrazin (JEAN-LOUIS ROUX) that also includes Archbishop Werner (ARMIN MUELLER-STAHL), known as the "Devil's Advocate" and his staunch doubts - especially related to the possibility of an American saint. They not only question Frank's findings regarding Helen, but also his qualifications for leading such an investigation. Despite mounting objections, the obligatory and necessary three miracles for consideration of sainthood, and in spite of his and other's doubts about himself, Frank continues on his steadfast course to make sure Helen has her posthumous shot of becoming a saint.