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.