On March 28, 1878 Pope Leo XIII appointed Keane as the fifth Bishop of Richmond when he was 38 years old. He was consecrated bishop on August 25, 1878 by Archbishop James Gibbons of Baltimore, who was his predecessor in Richmond. Bishops John Joseph Kain of Wheeling and Thomas Patrick Roger Foley of Chicago, were the principal co-consecrators. He established the Confraternity of the Holy Ghost in the diocese, and published A Sodality Manual for the Use of the Servants of the Holy Ghost in 1880. Despite opposition, he founded schools and churches for African-Americans. He lectured before Protestant groups throughout the diocese to lessen prejudice against the church. In 1884 he attended the Third Plenary Council of Baltimore. The following May he was appointed by the Council to the committee to establish a Catholic university in the United States.
Bishop Keane was appointed as the first rector of The Catholic University of America, Washington, D.C., in 1886 while he continued as Bishop of Richmond. On August 12, 1888 he was relieved of his responsibilities in Richmond and named Titular Bishop of Iasus so that he could focus his attention on establishing the new school. He soon gained a reputation as an administrator and an orator who was widely quoted in the press. At the same time he became aligned with the more progressive wing of the hierarchy because of the stances he took. He advocated for the Knights of Labor, took part in the Cahenslyism controversy, the quick Americanization of immigrants, the full representation of the Catholic Church at the Parliament of the World's Religions in Chicago and his positions on the school question. His democratic and liberal policies made him enemies with more conservative members of the U.S. Hierarchy and those at the Holy See, whence there came in 1896 a request for his resignation as rector.
Rome
On January 29, 1897 Pope Leo XIII named him the Titular Archbishop of Damascus. He spent the years 1897 to 1899 as canon of St. John Lateran, Assistant at the Pontifical Throne, and counsellor to the Propaganda. He lived in two rooms at the Pontifical Canadian College. He was attacked during the Americanism controversy that began to sweep through Europe "as a rationalist, throwing all dogma over to modern ideas." He fought, and won, the battle to clear his name. In 1899 he was relieved of his responsibilities in Rome to raise funds for Catholic University, which was facing financial difficulties.
On July 24, 1900 Pope Leo XIII appointed Archbishop Keane as the fourth bishop and second archbishop of Dubuque. He once again took a prominent part in the Catholic Young Men'sNational Union and in the Total Abstinence Union of North America, and lectured widely on temperance, education and American institutions. He encouraged postgraduate courses and ongoing education for priests, and doubled the faculty and buildings of St. Joseph's College. Twelve academies for girls and two for boys were constructed in the archdiocese. On January 15, 1902 the Diocese of Sioux City was established from the western half of the archdiocese. His friend and associate at Catholic University, the Rev. Philip Joseph Garrigan, was appointed Sioux City's first bishop. The current boundaries of the archdiocese would not be established until 1911 after his resignation. He served as archbishop until poor health forced him to request an auxiliary bishop or a coadjutor. No such appointment was made and he submitted his resignation instead. It was accepted by Pope Pius X on April 28, 1911, and he was named Titular Archbishop of Cius. He resided in the cathedral rectory in Dubuque until his death in 1918. Following his death Keane was buried at Mount Olivet Cemetery in nearby Key West. Archbishop Keane was succeeded by Bishop James John Keane of Cheyenne. Even though both men had the same last name, they were not related. Local citizens have also drawn comparisons between the two men. John Keane was known as "Sugar" due to his kind and generous nature. James Keane was nicknamed as "Hickory" due to his stern personality. A selection from his writings and addresses was edited by Maurice Francis Egan under the title Onward and Upward: A Year Book.
