In 1844, he led a delegation of students to Richmond Bridewell Prison, where he delivered an address to the imprisoned Daniel O'Connell.

[2] He completed his theological studies at Carlow College in 1852, his education supported by The Foreign Mission Fund, and was ordained a subdeacon.

In the same year he left Ireland for the United States, in the company of Patrick Feehan, later Archbishop of Chicago.

Following the war, he was transferred to St. John's Church[5] in St. Louis, and accompanied Archbishop Kenrick, as theologian, to the Second Plenary Council of Baltimore in 1866.

[7] During his 27-year-long tenure, Ryan erected 170 churches and 82 schools; increased the number of priests by 322 and nuns by 1,545; and oversaw a rise in the Catholic population from 300,000 to 525,000.

[3] During that time also the Roman Catholic High School for Boys was built, and put in operation; high school centers for girls taught by the different communities were established; a new central high school for girls was partly endowed and begun; St. Francis' Industrial School for Boys was endowed and successfully operated, the Philadelphia Protectory for Boys was erected; St. Joseph's Home for Working Boys was founded; a new foundling asylum and maternity hospital was built; a new St. Vincent's Home for younger orphan children was purchased with the archbishop's Golden Jubilee Fund of $200,000; a third Home for the Aged was erected; a Memorial Library Building, dedicated to the Archbishop, was begun at St. Charles Borromeo Seminary; and the three Catholic hospitals of the city doubled their capacity.

[3] In 1886, as chairman of the negotiating committee, he helped mediate a labor dispute between management and city trolley car workers, which resulted in a 10-hour work day and recognition of the right to unionize.

Known for his skill in public speaking, in 1879, Cardinal John McCloskey selected Ryan to make the address at the dedication of St. Patrick's Cathedral.

The Archbishop is described as "..a man of strong opinions who navigates the stormy waters of the nineteenth and early twentieth-century church without either making many enemies or compromising his basic beliefs.