[3] Byrne was chosen by Archbishop John Purcell to further his studies in philosophy and theology at the Pontifical North American College in Rome in 1865.

[5][3] He continued to teach at the seminary while also serving as chaplain to the Sisters of Charity at their motherhouse in Delhi (1869–1886) and pastor of St. Vincent de Paul Church in Sedamsville (1877–1886).

In collaboration with the rector of Mount St. Mary's, he translated Johann Baptist Alzog's Manual of Universal Church History.

[4] In 1879, Mount St. Mary's closed due to financial difficulty and Byrne went to reside at the Sisters of Charity motherhouse in Delhi, Ohio.

[1] On May 10, 1894, Byrne was appointed the fifth bishop of the Diocese of Nashville by Pope Leo XIII, covering the entire state of Tennessee.

Byrne received his episcopal consecration on July 25, 1894, from Archbishop Elder, with Bishops John Watterson and Camillus Maes serving as co-consecrators, at St. Joseph's Church in Nashville.