Response Surface Methodology (RSM) was employed in determining the effects of acidified blanching and pectinase enzyme treatments on the physicochemical properties, antioxidant activities, and sensory acceptability of Carica papaya juice. A two-factor central composite design (CCD) was used in this study (acidified blanching, 0.5–1.5%, w/v citric acid, and pectinase enzyme treatment, 10–30 ppm) to establish the optimum conditions for the processing of papaya juice. Acidified blanching and pectinase enzyme treatments are two variables which affect the physicochemical properties, antioxidant activities, and sensory acceptability of papaya juice. The changes in yield, clarity, antioxidant activities, and sensory acceptability of papaya juice were established by coefficients of determination, R2 as observed at 0.8707, 0.757, 0.7082 to 0.924, and 0.738 to 0.806, respectively. Increased acid concentrations in blanching water resulted in a positive quadratic effect (P < 0.05) on juice clarity. In comparison to untreated (control) papaya juice, acidified blanching and pectinase enzyme treatment resulted in papaya juice with greater total flavonoid content. However, increased pectinase enzyme concentrations were found to have a negative impact on sensory acceptance. The optimum predicted response conditions to produce papaya juice with high antioxidant activities and consumer acceptability were obtained from a combination of acidified blanching at 1% (w/v) citric acid and 20 ppm pectinase enzyme treatment. RSM is a valuable tool for optimizing the combination of acidified blanching and pectinase enzymatic treatments in producing papaya juice with high antioxidant activities.