Valorization of agricultural wastes is ongoing topic in industry. Determining the best conditions by artificial neural networks based optimization techniques is the key step to extract valuable compounds efficiently and to obtain high quality extracts. In this study, the response surface methodology (RSM)-desirability function (DF) and artificial neural network (ANN)-genetic algorithm (GA) approaches were compared in modeling and optimization the extraction parameters (temperature, time and ethanol concentration (ratio of ethanol to water, % v/v)) of phenolic compounds in pomegranate peels. The ANN-GA approach providing higher coefficient of determination and lower root mean square deviation showed better predictive capability than the RSM. The optimum time (81.4 min) and ethanol concentration (15.7%) of RSM-DF approach shifted to the lower levels (78.8 min and 15.3%) with the ANN-GA approach while the optimum temperature (54.0°C) shifted to a higher level (59.3°C). The use of these values provided total phenolic content of >1000 mg GAE L-1 and the corresponding antioxidant activity was 11 mmol TE L-1. As a result, increasing temperature up to a critical level decreased the extraction time and ethanol concentration, and it was determined that higher time-temperature combinations must be used for the complete water-based extraction of phenolic compounds from plant wastes in comparison to ethanol-water based extraction.