The ceremony will be held at 2 p.m. on Thursday. Handy was born in Florence in 1873.
Handy’s contributions to the blues have also been commemorated with Mississippi markers in Tutwiler, Clarksdale and Cleveland.
The Florence marker will also honor local natives Sam Phillips and Frank-O Johnson.
Handy, a band leader, is credited with being the first musician to put blues music into written form.
Handy’s “Memphis Blues” (1912) was among the first blues songs ever published. His most famous song, “St. Louis Blues,” ranks as one of the most-recorded songs of any genre.
Handy died in New York City in 1958.