Returning to England, he was licensed to preach as rabbi by Haham Benjamin Artom, in London, 1873; in the same year he was appointed preacher of the Great St. Helen's Synagogue of that city, but in December removed to New York, where he had accepted a call to the rabbinate of Shaaray Tefillah congregation (now the West End Synagogue); he entered upon his duties there January 1, 1874 as assistant minister to Rabbi Samuel M. Isaacs.

In 1888, he took part in the Field-Ingersoll controversy, writing for the North American Review an article entitled "In Defense of Jehovah.

"[1] In 1900, Mendes joined the staff of the Jewish Encyclopedia as revising editor and chief of the translation bureau, which positions he resigned in September 1902.

Along with Marcus Jastrow and Kaufmann Kohler, Frederick de Sola Mendes was one of the revisers of the Jewish Publication Society of America Version of the Bible.

[2] He also translated Jewish Family Papers: Letters of a Missionary, by "Gustav Meinhardt" (William Herzberg).