The 45-year-old joins Katy Perry, Alan Cumming and George Lopez as a voice actor in director Raja Gosnell's live-action/CGI hybrid film, reports Entertainment Weekly.
Neil Patrick Harris and Glee's Jayma Mays will play the movie's human leads.
Azaria, who has contributed voice work to The Simpsons, appeared in the 2009 comedies Year One and Night at the Museum 2: Battles of the Smithsonian. He will next be seen in drama Love and Other Drugs.
Belgian cartoonist Pierre Culliford created the Smurfs in 1958. The tiny blue characters were the stars of their own Hanna-Barbera cartoon series in the '80s.