Ordained in 1647, Fell was deprived of his fellowship at Oxford in 1648 for having fought with the Royalists against Oliver Cromwell during the English Civil Wars. Despite the opposition of the Cromwellian Protectorate to the Church of England, Fell continued to hold services throughout the Commonwealth. At the Restoration of the monarchy in 1660, he was made chaplain to King Charles II as well as canon and, later, dean of Christ Church, Oxford. Vice chancellor from 1666 to 1669, he became bishop of Oxford in 1676.

During this period Fell recovered for Oxford the reputation it had lost under Cromwell. He renovated numerous structures, including his own college of Christ Church, where he built the bell tower and hung the celebrated Great Tom bell, which continues to toll nightly at 9 o'clock. He began the construction of the Sheldonian Theatre, installed the university press in it, set up a type foundry, and encouraged the foundation of a paper mill nearby.

In addition to introducing fonts of type acquired abroad, he designed the “Fell” type, discontinued in the 18th century but rediscovered and reintroduced in 1874. Among books printed by the press are Fell's own editions of Theocritus, Aratus, the New Testament, Athenagoras, Theophilus of Antioch, Eratosthenes, St. Clement of Alexandria, and St. Cyprian. He was also the author of Interest of England Stated (1659) and The Vanity of Scoffing (1674).

Fell was the subject of the famous verse (cited in various forms by different editors; in fact based on a translation from the Latin poet Martial) by one of his Oxford students, the satirist Thomas Brown: