With her departure from the Kirk band in 1942, Williams settled in New York, where she opened her Harlem apartment to all types of musicians and was particularly encouraging to the experimentation of the young modernists. She helped to inspire and adapted to the revolutionary new style known as be-bop, which reduced many of her contemporaries to anachronisms, and also mentored many of the movement's founders, including Thelonious Monk, Bud Powell, Dizzy Gillespie, and Charlie Parker. (She crossed similar stylistic frontiers in 1977 when she performed a Carnegie Hall concert of duets with the avant-garde pianist Cecil Taylor.)
Her writing also continued to grow; along with Duke Ellington, she was a pioneer among jazz composers in producing extended works, such as the Zodiac Suite. In 1945, she debuted segments of the Suite on her weekly radio broadcast, Mary Lou Williams Piano Workshop, and performed three movements with the 70-piece New York Pops Orchestra during the June 1946 Carnegie Hall Pops Series. William's tours of England in 1952 and France in 1952, both widely covered in the European jazz press, place her in the tradition of Armstrong and Ellington two decades earlier in spreading jazz on the Continent.
In 1956, Williams underwent a spiritual conversion to Catholicism and gave up playing to concentrate on spiritual matters until reemerging in 1957 with a performance alongside Dizzy Gillespie at the Newport Jazz Festival. Compared to her rigorous schedule of touring over the previous 30 years, she played only sporadically over the next decade. She formed the Bel Canto Foundation to assist drug- and alcohol-dependent musicians in 1958. This initiative prefigured her founding of Cecilia Music, a publishing firm to release her compositions, and the establishment of Mary Records to issue her and other selected artists' recordings. Both of these events occurred in the early 1960s, when she also issued one of her later noteworthy recordings, the 1963 Mary Lou Williams Presents St. Martin de Porres.
Williams undertook several ambitious extended works during this period, including her 1971 composition Mary Lou's Mass, which was choreographed by Alvin Ailey and, in 1975, was performed during celebration of a Mass at St. Patrick's Cathedral. In 1977, her career undertook yet another significant turn. Duke University formalized William's role as an educator by appointing her as artist-in-residence, a position she held until her death in 1981. Duke permanently honored William's contributions by opening the Mary Lou Williams Center for Black Culture in September 1983 with an address by Nobel Prize winning author Toni Morrison.