The objective of the present project was to develop and optimize the Ibuprofen (IBU)-loaded nanostructured lipid carrier (IBU-NLCs) for sustained-release ocular drug delivery using a quality-by-design (QbD) approach. The BCS class II drug IBU was selected as the model drug for the preparation of IBU-NLCs by melt-emulsification and ultrasonication technique. Extensive preformulation screening of the components of NLC dispersion (i.e. solid and liquid lipid, surfactants, and osmolality agents) was performed. From the various lipids screened, Dynasan®114 and Miglyol®840 were selected as the most suitable solid and liquid lipid, respectively. These lipids, at a matrix ratio of 6:4, demonstrated a lower melting-point and crystallinity-index based on DSC, XRD, and compatibility studies. Various surfactants were evaluated, and among them, Kolliphor®HS15 demonstrated lower z-average particle size (PS) and polydispersity index (PDI), while Kolliphor®P188 resulted in a zeta potential (ZP) <-20 mV. Glycerol was selected from various osmolality agents due to its negligible effects on physicochemical properties of the optimized formulation. A Plackett-Burman design (PBD) was used for the initial screening of the critical variables, followed by a Box-Behnken design (BBD) for further optimization of the NLC dispersion. The optimized formulation demonstrated the PS of 147 nm, with narrow PDI (0.159), ZP of -25.7 mV, and an entrapment efficiency (EE) of 97.89%. In vitro diffusion of IBU from the optimized IBU-NLC dispersion showed a sustained-release of ∼51% for up to 12 h. Preformulation studies and a statistical hybrid-design approach was effectively applied to incorporate IBU in NLCs, resulting in a robust ophthalmic formulation with superior physicochemical properties.