The objective of the current study was to formulate solid lipid nanoparticles of oxybenzone to enhance its sunscreening efficacy while reducing its side effects. Solid lipid nanoparticles (SLNs) of oxybenzone were prepared by the solvent diffusion method. A complete 2(4) factorial design was used to optimize preparations. The study design involves the investigation of four independent variables, namely lipid type (Glyceryl monostearate, GMS; and Witepsol E85, WE85), lipid concentration (5 and 10%), polyvinyl alcohol (PVA) concentration (1 and 2%), and ethanol/acetone ratios (1:1 and 3:1, v/v), in terms of their effect on the particle size and entrapment efficiency. GMS was found to significantly increase the p.s. and EE%. SLNs prepared using 10% lipid had slower drug release compared to those prepared using 5%. The candidate oxybenzone-loaded SLN formula (SLN2) consisting of 0.5% oxybenzone, 10% GMS, 1% PVA, and ethanol/acetone (1:1, v/v) was then formulated into a gel and compared to the corresponding free oxybenzone nanosuspension and placebo SLN. The formulations were evaluated for skin irritation, in vitro sun protection factor, and ultraviolet A protection factors. The incorporation of oxybenzone into solid lipid nanoparticles greatly increased the SPF and UVA protection factor of oxybenzone more than five-fold while providing the advantage of overcoming skin irritancy problems.