Vemurafenib (VEM) is a recently licensed chemotherapeutic medication for the treatment of melanoma. Since the medicine is frequently taken orally, it can easily cause damage to important organs as well as to its low absorption. In this work, solid in oil nanodispersion (SON) was adapted to prepare a topical vemurafenib to target skin melanoma at early stages. SON is a unique oil-based dispersion that has been developed for revolutionary medication delivery methods. Both hydrophilic and hydrophobic bioactive drugs have the potential to be carried and delivered by this system. In our method, water and cyclohexane were removed from the W/O emulsion precursor containing 100 mg VEM by lyophilization, followed by redispersion of the surfactant–drug complex in another oil carrier, isopropyl myristate (IPM) to adjust VEM concentration (10 mg/ml). High energy techniques were used to produce VEM as SONs, with sucrose fatty acid ester surfactant (sucrose monolaurate, L195) in various ratios, as well as control was prepared by dispersing pure VEM in IPM (10 mg/ml). The preparations were evaluated for in vitro release through dialysis bag and ex vivo permeation experiments through Albino Wistar rat abdomen skin to simulate human skin as well as particle size, pH, partition coefficient, and entrapment efficiency. SON formula containing VEM-L195 complex in the ratio of 1:6.6 (F3) shows acceptable partition coefficient (Log P > 1), pH values appropriate for skin melanoma application, acceptable particle sizes, and good VEM entrapment efficiency. F3 was found to be released in vitro in a sustained pattern (9% in 1 h and 100% after 24 h) through the dialysis membrane compared to the control (25.9% in 1 h and 95.8% after 24 h). Ex vivo VEM permeability through rat abdomen skin was considerably (P < 0.05) higher for SON-F3 versus control (72% and 29%, respectively). Such SON formulation could be able to deliver VEM topically in an effective, sustained, and safe manner to treat early diagnosed skin melanoma.