With the increasing prevalence of antiparasitic-resistant cases and the limited availability of newly discovered or developed antiparasitic agents, it is crucial to focus research efforts on improving the efficacy of existing agents. Ivermectin (IVM) is commonly used to treat a wide range of parasites in both human and veterinary medicine, but its effectiveness is suboptimal, and the emergence of ivermectin-resistant parasites is a concern. In this context, the physico-chemical characteristics of the antiparasitic IVM were modified by nanocrystallization to improve its saturation water-solubility and skin penetration, which might eventually enhance the therapeutic efficacy through the dermal route. IVM-nanocrystals (IVM-NC) were prepared using microfluidization technique (top-down approach). The impact of different process/formulation variables on IVM-NC characteristics were optimized using D-optimal surface response statistical design. The optimized IVM-NC formulation was further lyophilized and evaluated using several in vitro and ex vivo techniques. The optimal IVM-NC produced small monodisperse particles with an average diameter of 186 nm and a polydispersity index of 0.4. The in vitro results indicated a significant enhancement in the saturation solubility and dissolution rate of IVM-NC, with an impressive 730-fold increase in the former and a substantial 24-fold increase in the latter. The ex vivo permeation study conducted on pig's ear skin demonstrated a 1.7-fold increase in the dermal deposition of IVM-NC. In addition, the lyophilized IVM-NC (IVM-NC-L) was integrated into a topical cream preparation at a concentration of 1% w/w, and the resulting drug release profile was compared to that of the corresponding marketed product. Overall, the formation of IVM-NC presents a promising approach to improving the effectiveness of topically applied IVM in treating local parasitic infections.