The Opuntia ficus-indica (OFI) prickly pear peel, is a residue product and was used as a substrate in solid-state fermentation (SSF) to obtain bioactive compounds of interest due to its antimicrobial and antioxidant activity. A Box Hunter & Hunter design to evaluate the independent factors was used. These factors were temperature (°C), inoculum (spores/g), humidity (%), pH, NaNO3 (g/L), MgSO4 (g/L), KCl (g/L) and KH2PO4 (g/L). The response factors were hydrolyzable and condensed tannins amount. In addition, the fermentation extracts the antioxidant and antimicrobial activity were evaluated. The results showed that the humidity (%), inoculum (spores/g) and temperature (°C) affect the release of hydrolyzable and condensed tannins. The treatments 13 and 16 were the best to accumulate condensed (43 mg/g) and hydrolyzable tannins (3.8 mg/g) respectively. Besides, the fermented extracts showed a higher antioxidant activity compared than the unfermented peel extracts, as well as a high inhibition versus E. coli, Alternaria sp. and Botrytis spp. The use of the fermentation process is a good alternative for the recovery of waste and the accumulation of bioactive molecules with potential industrial application.