The restoration process of burned and rough skin takes a long time and remains a critical challenge. It can be repaired through a combination of proper care, hydration, and topical therapies. In this study, a novel nanoemulsion was synthesized through the high-energy ultrasonication method. A total of five nanoemulsions (NE1−5) were prepared with varying concentrations of sandalwood oil, a nonionic surfactant (polysorbate 80), and water. Among them, NE3 had a number of appropriate physicochemical characteristics, such as physiological pH (5.58 ± 0.09), refractive index (∼1.34), electrical conductivity (115 ± 0.23 mS cm −1 ), and transmittance (∼96.5%), which were suitable for skin care applications. The NE3 had a strong surface potential of −18.5 ± 0.15 mV and a hydrodynamic size of 61.99 ± 0.22 nm with a polydispersity index of 0.204. The structural integrity and a distinct droplet size range between 50 and 100 nm were confirmed by transmission electron microscopic analysis. The skin regeneration and restoration abilities of synthesized nanoemulsions were examined by conducting an in vivo study on Sprague− Dawley rats. Exposure to NE3 significantly increased the healing process in burned skin as compared to untreated control and nonemulsified sandalwood oil. In another set of experiments, the NE3-treated rough skin became softer, smoother, and less scaly than all other treatments. Enhanced fatty acids, i.e., palmitic acid, stearic acid, and cholesterol, were recorded in NE3-supplemented burned and rough skin compared to the untreated control. The NE3 had outstanding compatibility with key components of skincare products without any stability issues. Its biocompatibility with the cellular system was established by the negligible generation of reactive oxygen species (ROS) and a lack of genotoxicity. Considering these results, NE3 can be used in cosmetic products such as creams, lotions, and serums, allowing industries to achieve improved product formulations and provide better healthcare benefits to humanity.