Lung cancer is the leading cause of cancer-related death in the world, and approximately 80% to 85% of lung cancers are non-small cell lung cancer (NSCLC). Paclitaxel (PTX) has been widely used for the treatment of NSCLC. It is classified as a BCS class IV drug and offers a low therapeutic index. The present investigation demonstrates development of orally administered PEGylated, PTX loaded solid lipid nanoparticles (PTX-SLNs). A Box-Behnken design was applied to systematically optimize PTX-SLNs. Drug concentration, emulsifier concentration and homogenization pressure were selected as an independent variables, and particle size, % entrapment efficiency (%EE) and % drug loading (%DL) were selected as dependent variables. The particle size of optimized PTXSLNs was found to be 401 ± 12 nm, with %EE of 86.63 ± 2.58%, and %DL of 7.42 ± 0.11%. The developed PTX-SLNs exhibited anti-lipolytic effect due to its stabilization by MPEG2000-DSPE. Moreover, the in vitro GI stability studies revealed good stability of PTX-SLNs in various GI tract media. The in vitro drug release studies revealed controlled release profile with Weibull model release kinetics. In vitro cytotoxicity studies in H1299 cell lines revealed significant decline in IC50 values of PTX-SLNs treated cells as compared to pure drug, thus revealing an improved efficacy of the developed systems.