The markedly low oral bioavailability of domperidone (anti-emetic drug) is associated with rapid first-pass metabolism in the intestine and liver. To counteract such affects, there is a need to devise a strategy to enhance absorption and subsequently bioavailability. Thus, the current study was aimed at synthesizing phytosomes consisting of phosphatidylcholine and piperine (a P-glycoprotein inhibitor). Phytosomes were prepared by salting-out method. The developed phytosomes were extensively characterized for size, zeta potential, polydispersity index, entrapment efficiency (EE %), infrared spectroscopy, X-ray diffraction, in-vitro drug release, ex-vivo permeation, in-vivo pharmacokinetic and toxicity. The engineered formulations of phytosomes with piperine exhibited a significant improvement in oral bioavailability of domperidone (79.5%) in comparison with the pure drug suspension under the same conditions. Pharmacokinetic parameters such as maximal plasma concentration (Cmax) and the plasma concentration (estimated from area under the curve; AUC) of domperidone have been greatly increased relative to drug alone. The improved drug absorption was attributed to inhibition of P-glycoprotein transporter. The findings of current research work suggest that the optimized phytosomes based drug delivery containing phytochemicals as bioenhancers have the potential to improve bioavailability of poorly bioavailable drugs that are substrate to P-glycoprotein.