Born and raised in Lowell, Massachusetts, William O'Connell was the youngest of eleven children of John and Bridget O'Connell. He later graduated from Boston College and traveled to Rome for further studies at the American College. After his ordination he remained in Rome for a time, during which he developed influential friendships with several clerics who helped shape his career.

After Fr. O'Connell's return to the United States, he served as a curate in the Massachusetts parishes of Medford and Boston's West End. In 1895, he returned to Rome until his appointment as Third Bishop of Portland. He was consecrated a bishop at the Lateran Basilica on May 19, 1901, then installed in Portland at the Cathedral on July 4, 1901.

During Bishop O'Connell's years in Portland, the Cathedral underwent its first renovations. Frescoing in the sanctuary and retouching the continuous frieze under the large windows were some of the minor changes made. The most memorable change was the addition of the beautiful Immaculate Conception signature window and the magnificent Altat of the Sacred Heart immediately in front of it. These were Bishop O'Connell's gifts to the Cathedral in 1902. His name is on a brass plaque at the bottom of the altar, as well as on the bottom right-hand panel of the window.

Bishop O'Connell's time in the Portland Diocese was brief. In April 1906 he was transferred to Boston as Coadjutor Archbishop to Archbishop John Joseph Williams. Upon Archbishop Williams' death in 1906, he was named Cardinal in the Archdiocese of Boston where he remained until his death in 1944. He is buried on the campus of Saint John's Seminary in Brighton, Massachusetts.