The narrative is based on two historical figures of the late 19th century, Jean-Baptiste Lamy and Joseph Projectus Machebeuf, and rather than any one singular plot, is the stylized re-telling of their lives serving as Roman Catholic clergy in New Mexico.

The action then switches to the primary character, Bishop Jean Marie Latour, who travels with his friend and vicar Joseph Vaillant from Sandusky, Ohio to New Mexico.

While the narrative speaks of Vaillant positively, it also alludes to his willingness to acquire (he "forces the hand" of a landowner into giving him and Latour two prize mules, Angelica and Contento, chastises the widow Dona Isabella Olivares for refusing to assert her rights under her husband's will and thereby blocking the church from its testamentary share, and goes on frank "begging trips" to acquire money) and near the end of the novel his questionable financial behaviour receives an investigation from Rome.

Latour, again presented favourably, nevertheless does operate with a view to politics: he successfully canvasses donations to build a Romanesque cathedral in Santa Fe according to his own desires (he chooses the stone and brings the architect Molny from France to complete it), and bides his time to remove dissenting priests and help a poor Mexican slave-woman named Sada until he is in a position of political strength (his help of Sada is never described in the novel).

All three escape, and Scales is hanged for the murder of four of his former guests, while Magdalena ultimately serves nuns whom Latour brings from Europe and who run a school in Santa Fe.

[9] James Paul Old of Valparaiso University uses Death Comes for the Archbishop as a literary example of the notion that religious faith is able to develop and maintain strong social bonds in nascent democratic political orders.

"[11] In developing a theory that Cather had questioned her own gender in the 1920s, Patrick W. Shaw suggests that "fundamental double entendres" and "elaborate image clusters" throughout the novel support a reading of sexual disregularity and ambiguity.