Abstract In this study, natural membranes such as the outer membrane of Prunus persica (peach) and Lycopersicon esculentum (tomato), the inner layer of the egg of Gallus domesticus (hen) and the middle membrane of the Allium cepa (onion) were used as controlling barriers for permeation of some model drugs with different MW and lipophilicities. Drug permeation studies were done by using modified Franz diffusion cell. The permeation of drugs through these natural membranes was compared to permeation of them through human skin and synthetic cellophane membrane. Results showed that the rate and amount of diclofenac permeated through onion membrane was not significantly different from that with tomato ( p > 0.17), egg ( p > 0.29) and human skin ( p > 0.93). Permeation of diclofenac through tomato skin and cellophane was not significantly different ( p > 0.35). Permeation of diclofenac through all studied membranes except for human skin that follows the Fickian kinetic followed non-Fickian mechanism and their permeabilities were not significantly different from each other ( p > 0.05). Permeation of metronidazole through onion membrane and tomato skin were not significantly different from human skin ( p > 0.053 and 0.38, respectively). All membranes were significantly different from each other ( p < 0.0001) for permeation of erythromycin as a relatively large molecular weight and lipohilic molecule through human skin and other studied membranes. Permeation of diclofenac through human skin and metronidazole through egg and tomato skin followed Fick's first law. Diffusion of diclofenac through onion, tomato, egg, cellophane, and peach; metronidazole through onion, peach, cellophane, and human skin, and erythromycin through all studied membranes followed non-Fickian mechanism for diffusion. Statistical analysis showed the most similarity between onion and human skin for diclofenac, tomato and human skin for metronidazole, onion and cellophane for erythromycin.