Microwave vacuum drying of pomegranate peel was studied through this work and the drying process was modeled with the aid of response surface methodology (RSM) and artificial neural network (ANN) method. The drying experimental runs were performed on varied ranges of microwave power (175, 330, and 485 W) and vacuum pressure (10, 15, and 20 kPa) using a face-centered composite design. The influence of process parameters on five target responses, namely: total hydrolysable tannin (THT), color change (ΔE), maximum temperature evolved (T max ), effective moisture diffusivity (D eff ), and specific energy consumption (SEC) were analyzed. For microwave power and vacuum, the optimal conditions attained with aid of RSM and ANN were 260 W, 15.59 kPa, and 287 W, 19 kPa, respectively. The THT retention, ΔE, T max , D eff , SEC determined with RSM and ANN optimized values were 78.51 mg TAE/g of DW, 13.48, 67.02°C, 3.38 × 10 −6 m 2 /s, 20.02 kWh/kg and 90.32 ± 0.35 mg TAE/g of DW, 12.488, 64.83°C, 5.64 × 10 −6 m 2 /s, 20.01 ± 0.33 kWh/kg, respectively. The influence analysis explained that pomegranate peel dried at optimized ANN conditions of microwave power 287 W and vacuum 19 kPa possessed improved physicochemical properties and was efficient in terms of energy consumption compared to peel dried using RSM suggested conditions. Furthermore, the major criterion for evaluation between RSM and ANN tools in this study was the goodness of fit. The value for R 2 produced via RSM varied between 0.8354 and 0.9870, whereas subsequent R 2 in the case of ANN was considerably greater, varying between 0.9213 and 0.9956. The mean square error value displayed the minimum value in the case of ANN compared to the RSM model. These signified rather greater exactness and predictive capability of the ANN tool. Fourier transform infrared analysis established the existence of peaks between 3,308.92 and 908.89 cm −1 and high-performance liquid chromatography showed that pomegranate peel produced using microwave vacuum drying contains a good amount of gallic acid and tannic acid derivative compounds. Scanning electron microscopy elucidated that the combined microwave vacuum effect resulted in the formation of bigger pores on the peel surface ensuing in elevated extraction of THT at reduced energy consumption.