Berberine hydrochloride (BH) possesses various pharmacological properties including anticancer; unfortunately, it has low oral bioavailability and potential side effects for its parenteral administration. Nanoscale delivery carriers can increase the oral bioavailability of BH. Chitosan has interesting biopharmaceutical properties such as nontoxicity, biocompatibility, biodegradability, and mucoadhesiveness, and the ability to open epithelial tight junctions. This study aims to engineer a chitosan-coated nano-liposomal carrier for the oral delivery of BH. The engineered formulation had a size in the nanoscale range. Chitosan-coated nano-liposomes displayed better stability and slower BH release in the simulated gastrointestinal (GI) environment as compared to the uncoated ones. All values of pharmacokinetic analysis for chitosan-coated nano-liposomes were higher than for uncoated ones. These findings demonstrate that chitosan-coated nano-liposomes are more efficient than uncoated ones for the oral delivery of BH. It can be concluded that the stability and delayed BH release in the simulated GI environment were improved with engineered chitosan-coated nano-liposomes. Moreover, since desirable in vitro and in vivo characteristics were achieved, they are promising release devices for the oral delivery of BH increasing the bioavailability of the drug.