This study aimed to optimize a self-nanoemulsifying drug delivery system (SNEDDS) for curcumin (CUR) to tackle its poor solubility and bioavailability. Preliminary screening identified optimal components based on solubility, emulsifying efficiency, and pseudo-ternary phase diagram construction. Optimization was performed using Design Expert® software, considering droplet size, Polydispersity Index (PDI), and transmittance as responses. The formulation, comprising Caprylol 90 and Capmul MCM C-8 oils, Cremophor EL, Tween 80 surfactants, and Gelucire 48/16 co-surfactant, demonstrated a globule size of 181.3 ± 6.5 nm, PDI of 0.27, and negative zeta potential (-11.7 mV), ensuring stability and uniformity. Morphological analysis confirmed the presence of uniform, spherical oil globules with a high drug content of 98.2 ± 1.64%. In vitro studies revealed a rapid drug release, surpassing 85% within 2 hours, notably higher than plain CUR. Pharmacokinetic assessment in vivo indicated enhanced Cmax, AUC, t1/2, and MRT for CUR-loaded SNEDDS, suggesting improved bioavailability and extended systemic exposure. These results highlight the potential of the optimized SNEDDS formulation in ameliorating clinical outcomes, particularly in conditions like mucositis, where enhanced drug delivery is critical.