In this study, pomegranate peel as a traditional natural remedy was extracted and encapsulated in proniosomal systems in order to improve its stability against harsh environmental conditions. Pomegranate peel was extracted by using sonication as a green extraction technology and the antioxidant activity of the obtained extract was evaluated to be 85.37% by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. Proniosomal powder was prepared based on the slurry method with a mixture of non-ionic surfactants namely span 60 and tween 20 in combination with cholesterol as a bilayer stabilizer. Proniosome-derived niosomes were achieved by hydration of the powder with water. The obtained vesicles were evaluated for their particle size, morphological observations, entrapment efficiency, cytotoxicity assay, DPPH antioxidant activity and, physical stability at 4 °C for 28 days. The results demonstrated that the proniosome-derived niosomes were of small size (198.16 nm for unloaded and 411.3 for extract loaded), quite homogeneous (PDI = 0.188 for unloaded and 0.216 for loaded) with highly negative charged spherical vesicles and showed appropriate physical stability during the time of storage. The encapsulation efficiency was 68.43±0.24% and the cytotoxicity assay proved that the formulations were not toxic against 3T3 fibroblast cells in the applied concentration.