Hypertension is a serious cardiovascular event which refers to rise in the arterial blood pressure. Perinodopril which has been classified as calcium channel blocker is utilized in the treatment of hypertension. Perinodopril comes under BCS class II drug (low solubility/high permeability) which shows variable absorption pattern due to solubility limitation. Therefore, nanostructured lipid carrier (NLC) of Perinodopril was developed which is suitable for drug with high log P value as it offers the advantage of high drug entrapment and loading capacity to lipophilic drugs. Tween 80 and Poloxamer 188 were reportedly P-gp efflux inhibitors which would be an added feature to the property of Perinodopril -NLC thus enhancing drug availability across intestine. Therefore, the objectives of the present work were to develop an optimized Perinodopril -NLC using Quality by design (QbD) and evaluating it for enhancement in intestinal uptake and solubilisation fate (in physiologically simulating gastro intestinal milieu) of Perinodopril which would further enhance the oral bioavailability. Physicochemical characterization of the drug by means of UV spectra, DSC and FT-IR concluded that Perinodopril is pure and authentic. Both medium chain triglycerides (MCT) and long chain triglycerides (LCT) were used in the solubility studies of Perinodopril.