BACKGROUND: Mebendazole (MBZ) is an anthelmintic drug that was repurposed as an anti-cancer agent. OBJECTIVES: This study aimed at formulating MBZ into stearylamine tailored spanlastics dispersed in nanogel for enhancing MBZ anti-tumor efficacy against skin cancer. METHODS: MBZ spanlastics were prepared by thin film hydration using 2(1) × 3(1) factorial design. The formulation variables were the total amount (mg) of Span 60 and Tween 80 in the formulations and the ratio between Span 60 and Tween 80. RESULTS: Optimal spanlastics formulation was composed of 400 mg of Span 60 and Tween 80 in a ratio of 2:1 and showed EE% of 78 ± 2.9% and PS of 284.00 ± 35.36 nm. Stearylamine (20 mg) was added to the optimized formulation and showed acceptable positive charge (zeta potential = 47.53 ± 1.50 mV). It was dispersed in 30% Tetronic(®)1107 solution to form a nanogel. MBZ nanogel was assessed for their cytotoxic effect on cell proliferation against human malignant melanoma and epidermoid carcinoma cell lines and showed 38.70 ± 1.70% and 48.60 ± 0.50% (respectively) cell proliferation compared to the control group (100%). Finally, its permeation through Wistar rat skin was tested. CONCLUSION: SA-spanlastics nanogel holds potential as an effective nanocarrier for boosting MBZ anti-cancer efficacy.