Pomegranate peels are disposed of as waste even though it is an eminent source of total hydrolysable tannins (THT) and possesses a great worth for recycling. The present study was carried out with the hypothesis that pulsed system ultrasound-assisted extraction (PSUAE) technique optimization would aid in retaining high extract yield and THT recovery yield from pomegranate peel extract (PPE) with enhanced antioxidant potential. The extraction was performed at various conditions regarding solvent concentration (30–90% of acetone), solvent-feed ratio (10–30 mL/g), extraction time (10–20 min), and ultrasound amplitude (40–80%) for maximum extract yield, THT and antioxidant activity (AA). To model and optimize the process conditions tools namely response surface methodology (RSM) and artificial neural network (ANN) were applied. For solvent concentration, solvent-feed ratio, extraction time, and amplitude the optimal conditions attained with aid of RSM and ANN were: 56%, 26.5 mL/g, 15 min, 55%, and 45%, 23 mL/g, 15 min, 50% respectively. The extract yield and THT content determined with RSM and ANN optimized values were 51.2%, 86.4 mg TAE/g, and 62%, 98.1 mg TAE/g, respectively. The mean square error value displayed the minimum and R2 exhibited maximum value in case of ANN compared to RSM model. PSUAE significantly augmented the AA of PPE to 77.2 ± 0.50% compared to 49.7 ± 0.35% of conventional extraction. FTIR and HPLC analysis established that PPE produced from PSUAE contains a significant amount of THT compounds (gallic acid and tannic acid derivative). SEM elucidated that the sonication effect resulted in peel cell wall disruptions ensuing in elevated extraction of THT. Therefore, this pulsed mode of ultrasound extraction could be regarded as an easy, cost-effective, and competent technique for the extraction of preferred natural THT from pomegranate peels that possess high prospective to be applied in food and nutraceutical formulations.