Simvastatin is one the most commonly used drugs for treatment of hypercholesterolemia but suffers from low bioavailability (about 5%) owing to poor aqueous solubility and extensive first pass metabolism. Glycerylmonostearate/chitosan hybrid olive oil cored nanocapsules were fabricated by a self-assembly method. Nine batches were successfully produced based on glycerylmonostearate/chitosan ratio and olive oil concentration. Selected formulation was and evaluated for oral bioavailability enhancement and pharmacodynamics. Glycerylmonostearate/chitosan ratio strongly influence the particle size and encapsulation of the formulations. Higher concentrations of olive oil produced larger particle size, heterogeneous distribution and higher encapsulation. Embedding of SIM in system matrix with existence in amorphous state was verified by DSC and FTIR tools. Selected formulation significantly enhanced SIM oral bioavailability with a 3.27-time higher in AUC when compared to SIM suspension. In addition, in vivo prolonged effect was verified by higher elimination half-life and mean residence time in plasma. Furthermore, pathological changes in liver and aorta associated with Poloxamer 704 injection have been mostly corrected. Serum lipid profile, liver function enzymes and oxidative stress were also restored. According to these results, glycerylmonostearate/chitosan hybrid olive oil cored nanocapsules proved to be a promising formulation strategy to significantly enhance SIM peroral bioavailability and therefore therapeutic efficacy.