The effect of high pressure processing on total antioxidant activity, phenolic and flavonoid content of black grapes juice was studied. Response surface methodology (RSM) was used for designing the experiment keeping high pressure (400–600 MPa), temperature (40–60 °C) and processing time (2–4 min) as independent variables. The data obtained were analysed using multiple regression technique and quadratic models were found to fit well (R2, 85.61–96.65%) in describing the effect of high pressure, temperature and time on total antioxidant activity, phenolics and flavonoids. The optimum levels were found to be 550 MPa, 44 °C and 2 min for pressure, temperature and processing time, respectively (desirability, 95.00) for getting the maximum retention of total antioxidant activity, phenolics and flavonoids in the juice. The experimental and predicted valued of responses showed high correlation (R2, 99.26–99.90%) at the optimised levels of the variables.