The objective of this study was to optimize different vacuum drying conditions for cocoa pod husk and cocoa bean shell in order to enhance these by-products for commercial applications. To carry out the optimization, the response surface methodology was applied using a Box–Behnken experimental design with 15 experiments for which different conditions of temperature (X1), drying time (X2) and vacuum pressure (X3) were established. The response variables were the content of total polyphenols, the content of flavanols and the radical scavenging activity evaluated in the extracts of the different experiments. Temperature (50–70 °C), drying time (3–12 h) and vacuum pressure (50–150 mbar) were considered as independent variables. The main factors affecting the response variables were temperature, followed by vacuum pressure. For the content of polyphenols, the optimal response values predicted for the cocoa pod husk was 11.17 mg GAE/g with a confidence limit (95%) of 9.05 to 13.28 mg GAE/g (optimal conditions: 65 °C, 8 h and 75 mbar), while for the cocoa bean shell cocoa was 29.61 mg GAE/g with a confidence limit (95%) of 26.95 to 32.26 mg GAE/g (optimal conditions: 50 °C, 5 h and 100 mbar). Therefore, results of this study suggest a high content of phenolic compounds obtained from these by-products that show relevance as functional ingredients for application in the food, nutraceutical, and cosmeceutical industries.