Originally dubbed The Church, the venue is now Babeville.
The building houses her music label, Righteous Babe Records, and Hallwalls Contemporary Arts Center.
DiFranco's first public concerts in the space were set for Tuesday and Wednesday in Asbury Hall, the former sanctuary. Both concerts were sold out.
The 36-year-old singer reopened the building in January after she and her manager, Scot Fisher, saved it from the wrecking ball and, with the city's help, poured $10 million into its renovation.