Ordained a priest in 1844 and appointed bishop of Mainz in 1850, Ketteler attracted national attention by his sermons and writings. He was interested in political and social problems and was a member of the Frankfurt National Assembly (1848) and later of the German Reichstag (1871–72). His concern was for the working class, whose well-being, he proposed, was the church's responsibility. His opposition to papal infallibility caused him to become one of the leaders of the “inopportunists” (those against the “infallibilists”) at the first Vatican Council (1869–70).

His views on social reform were most comprehensively expressed in his book Die Arbeiterfrage und das Christenthum (1864; “The Labourer Question and Christianity”), which strongly stimulated the interest of German Roman Catholics in social problems. Ketteler's paramount concern for the need of a Christian foundation supplied the quintessence of his other writings and his sermons. His most important works were edited by Johannes Mumbauer, Wilhelm Emmanuel von Kettelers Schriften (3 vol., 1911; 2nd ed., 1924).