The episodic, nearly plotless narrative of Death Comes for the Archbishop begins with a Prologue in which the Vatican assigns Father Jean Marie Latour, a French Jesuit missionary priest serving in Sandusky, Ohio, to the New Mexico territory following the region's annexation to the United States. Latour is elevated to bishop, and sets out for Santa Fe with Father Joseph Vaillant, a personal friend from the pair's schooldays.
Latour and Vaillant are charged with reinvigorating the Catholic Church in the region after nearly three centuries of neglect. Although the region can still be considered predominantly Catholic, the faith has been usurped by rogue priests who have taken mistresses with whom they have fathered children, abused the Mexican and Indian natives, and exhibited greed.
Latour sets out to impart a disciplined approach to Catholicism in the Southwest, meeting resistance from Padre Gallegos in Albuquerque, Padre Antonio Jose Martinez of Taos, and Padre Lucero of Arroyo Hondo. Gallegos is a hedonistic glutton and gambler, Martinez a promiscuous libertine, and Lucero a greedy liar.
It takes Latour nearly a year to travel from Ohio to New Mexico, traveling down the Mississippi River to New Orleans, and then on to Galveston by steamboat. He loses most of his possessions in Galveston, when the steamboat is wrecked, but continues to travel by land across Texas and into the New Mexico territory with a mare and a pack mule.
