In the present investigation, spray drying independent operating conditions such as the inlet air temperature (A-IAT 130, 150 and 170 °C), outlet air temperature (B-OAT 60, 70 and 80 °C), needle speed (C-NS 3S, 4S, 5S), maltodextrin concentration (D-MD 10, 15, 20 %), pump speed (E-PS 5, 10, 15 mL/min) and water/grape pomace ratio (F-W/GP ratio 10, 15, 20) were optimized to develop the spray-dried grape pomace powder (SDGPP) with maximum yield. The impact of these conditions on total phenolic contents (TPC), total flavonoid contents (TFC), and antioxidant activity (DPPH· values) of SDGPP samples were analyzed. The independent spray drying factors (IAT, OAT, NS, MD, PS, and W/GP ratio) impart a strong direct effect (p ≤ 0.05) on powder yield, TPC, TFC, and DPPH· values. The interaction effects (A × B, A × C, A × D, A × E, A × F, B × C, B × D, B × E, B × F, C × D, C × E, C × F, D × E, D × F, and E × F) of independent variables were noted non-significant (p ≥ 0.05) for response values. After validation of the model and verification of results, the independents' variables were found in the range of 170 °C (IAT), 80 °C (OAT), 4S (NS), 15 % (MD), 10 mL/min (PS) and 15 (W/GP ratio) for yield (64.7 ± 1.18 %), TPC (7.66 ± 0.53 mg GAE/g), TFC (3.19 ± 0.30 mg CE/g) and DPPH· 140.3 ± 1.59 (100 µL/mL), respectively. The decrease in TPC, TFC, and DPPH· values of SDGPP samples was noted during 60 days of storage at 25 ± 2 °C and 65 ± 5 % RH (p ≤ 0.05) but not greater than unprocessed samples. It could be concluded that the protection of phenolic contents and retention of antioxidant activity of dried powders can be achieved at optimized spray drying conditions for discerning food and byproduct processing industries.