In the present study, Atazanavir sulfate-loaded solid lipid nanoparticles (ATZ-SLNs) were developed and characterized for oral bioavailability enhancement and lymphatic absorption. ATZ-SLNs were formulated by emulsion-solvent evaporation technique using hydrogenated castor oil and sodium oleate. The optimized formulation had a mean particle size of 190.1 ± 2.45 nm, the zeta potential of −42.63 ± 2.46 mV and entrapment efficiency of 94.26 ± 2.12%. Transmission electron microscopy and Field emission-scanning electron microscopy morphology indicated discrete and round structures without aggregation. In-vitro drug release study showed controlled drug release of 80.36% in 12 h in simulated intestinal fluid. Cell-line study in Caco-2 cells showed increased permeability upon SLN formulation and mode of cellular uptake of SLN as clathrin and caveoli mediated endocytosis. In-vivo pharmacokinetic study in rats indicated increased oral bioavailability using ATZ-SLNs by 200% compared to suspension formulation. A lymphatic transport study revealed that SLNs were transported via lymphatic vessels. In organ biodistribution study, peyer's patch region showed a 4.5 fold higher uptake of ATZ through ATZ-SLNs formulation than non-peyer's patch region and high accumulation in spleen and brain. This delivery approach could maximize the drug concentrations to the lymphatic system leading to effective therapy for HIV.