This study aimed to incorporate nanocapsules containing 3,3′-diindolylmethane (DIM) with antitumor activity into a bilayer film of karaya and gellan gums for use in topical melanoma therapy. Nanocarriers and films were prepared by interfacial deposition of the preformed polymer and solvent casting methods, respectively. Incorporating DIM into nanocapsules increased its antitumor potential against human melanoma cells (A-375) (IC50 > 24.00 µg/mL free DIM × 2.89 µg/mL nanocapsules). The films were transparent, hydrophilic (θ < 90°), had homogeneous thickness and weight, and had a DIM content of 106 µg/cm2. Radical ABTS+ scavenger assay showed that the DIM films presented promising antioxidant action. Remarkably, the films showed selective bioadhesive potential on the karaya gum side. Considering the mechanical analyses, the nanotechnology-based films presented appropriate behavior for cutaneous application and controlled DIM release profile, which could increase the residence time on the application site. Furthermore, the nanofilms were found to increase the permeation of DIM into the epidermis, where melanoma develops. Lastly, the films were non-hemolytic (hemolysis test) and non-irritant (HET-CAM assay). In summary, the combination of karaya and gellan gum in bilayer films that contain nanoencapsulated DIM has demonstrated potential in the topical treatment of melanoma and could serve as a viable option for administering DIM for cutaneous melanoma therapy.