Pomegranate peel is an important source of polyphenols of remarkable interest in the food, pharmaceutical and cosmetic industry. The improved extraction of total polyphenolic compounds (TPC) from pomegranate peel by solid-state fermentation (SSF) was achieved. The Box, Hunter and Hunter (BHH) followed by the central composite design (CCD) processes were performed to assess the effect of the process variables on TPC release. The statistical designs indicate that the best TPC extraction (234.85 mg GAE/gdm) by means of SSF occurs at 42 °C, 50% moisture, 5.0 pH, mineral solution (g/L): NaNO3 (3.83), KH2PO4 (1.52), MgSO4 (4.66) and KCl (1.52) at 36 h. Under the best fermentation conditions TPC (248.78 ± 1.24 mgGAE/gdm) increased 5.96-fold more than values previously reported and antioxidant activity (AA) increased 5.81-fold compared to the value obtained before the SSF optimization. High-value citric acid, α and β punicalin, α and β punicalagin, punigluconin, galloyl-HHDP hexoside and ellagic acid molecules were identified. The increased extraction of TPC by SSF provides a suitable alternative for the valorization of pomegranate peel through the recovery of molecules with high added value with potential use in the food, pharmacy and cosmetic industries; a diversification in the use of food agroindustry by-products is obtained as an approach to the circular economy model through biotechnological processes.