<p>Melanoma, the most aggressive skin cancer, requires novel and effective treatment strategies. This study developed an optimized mesoporous silica nanoparticle (MSN)-based system for the delivery of curcumin and quercetin, two polyphenolic compounds with anticancer properties, to enhance their transdermal delivery. MSNs were synthesized using the sol-gel method and optimized via a Box-Behnken design, resulting in nanoparticles with an average size of 172.92 ± 23.74&#xa0;nm and a polydispersity index (PDI) of 0.291 ± 0.026. Drug entrapment efficiencies were 46.25 ± 3.55% for curcumin and 50.35 ± 4.65% for quercetin. In vitro drug release showed sustained profiles, with 8.49 ± 0.80% of curcumin and 12.87 ± 1.27% of quercetin released over 24&#xa0;h. Ex vivo skin permeation studies revealed a 2.6-fold and 2.25-fold increase in permeation for curcumin and quercetin, respectively, compared to free drugs. Cytotoxicity studies demonstrated enhanced efficacy of the co-delivered MSNs formulations, with IC₅₀ values of 91.351 ± 6.114 µM for curcumin-loaded MSNs and 163.313 ± 12.880 µM for quercetin-loaded MSNs against A375 melanoma cells, significantly lower than those of their free drug counterparts. These findings suggest that MSN-based delivery systems offer a promising strategy for the topical treatment of melanoma by improving drug permeation and therapeutic efficacy.</p>