Nanocarriers are systems that deliver therapeutic agents to specific body sites, improving drug effectiveness and reducing side effects. Nanoemulgels, combining nanoemulsions and gels, are ideal for topical delivery. Nanoemulsions, made of oil, water, surfactants, and cosurfactants, enhance hydrophobic drug solubility, while the gel provides good skin adherence. Swertiamarin, incorporated into a nanoemulgel, benefits from improved solubility, stability, and skin penetration, targeting oxidative stress and mitochondrial dysfunction, which could aid in conditions like endometriosis. The study focused on optimizing a nanoemulsion-based topical formulation of Swertiamarin, evaluating solubility, stability, and pharmacokinetics through preformulation studies, UV absorption, FTIR analysis, and in-silico pharmacokinetic profiling. Materials and methods included formulating various nanoemulsions (NE1 to NE5), with NE4 being the most effective based on its entrapment efficiency (87.079 ± 1.834%). Visual and pH assessments showed good physical stability and compatibility with human skin. Spreadability and density tests confirmed that NE4 was optimal for topical application. Particle size and zeta potential measurements (341.9 nm and -17.09 mV, respectively) indicated stability and uniform particle distribution. Furthermore, in-silico molecular docking revealed strong interactions between SWM and the mitochondrial protein MT-CO1, suggesting SWM’s potential to modulate oxidative stress. The study concluded that the developed NE4 nanoemulgel was stable, highly effective for drug delivery, and promising for further investigations in treating conditions related to mitochondrial dysfunction, such as diabetic nephropathy.