The current study explores the potential of nanostructured lipid carriers (NLCs) for oral bioavailability enhancement of olmesartan medoxomil (OLM) by systemic design approach. OLM-NLC was successfully prepared with optimized process parameters (i.e. amount of liquid lipid, total amount of lipid, drug content and surfactant concentration) using the Box-Behnken design of experiments for different response parameters (i.e. particle size, Polydispersity index and entrapment efficiency). Further, optimized formulation was validated which depicted nano size, homogenous distribution with optimum entrapment efficiency. OLM-NLC was characterized by different techniques viz. differential scanning calorimetry (DSC), powder X-Ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which showed reduced crystallinity of the drug with smooth spherical appearance of nanoparticles. Formulation was found to be stable in simulated gastric fluids as no significant changes were found in size, PDI and entrapment efficiency. In vitro release showed extended release of OLM from OLM-NLC. In vitro cellular uptake study revealed 5.2 folds higher uptake of nanoparticles as compare to the free drug, when incubated with Caco-2 cells. In vivo performance showed that AUC and C of OLM-NLC were found significantly (P<0.01) higher as compare to the free drug. Overall, the present study successfully reports the improvement of oral bioavailability of olmesartan medoxomil.