A hydrogel based on polymeric nanocapsules containing 3,3′-diindolmethane (DIM) was developed for the treatment of skin inflammatory disorders. Nanocapsule suspensions were prepared by interfacial deposition of preformed polymer method and thickened using locust bean gum (3%) to obtain hydrogels. The hydrogels showed satisfactory DIM content (1 mg/g), pH in the neutrality range (6.59–6.82), particle size in nanometric scale (around 140 nm) and non-Newtonian pseudoplastic behavior. In addition, nano-based formulations showed a greater amount of DIM released in vitro, and a smaller amount of active in the dermis was observed in the evaluation of skin permeation. The HET-CAM assay classified the hydrogels as non-irritating. Finally, the performance of hydrogels in two in vivo models of skin inflammation was evaluated. The evaluation of the anti-inflammatory effect in a model induced by croton oil showed that the nano-based hydrogels maintained the DIM activity, reducing ear edema and leukocyte infiltration. Regarding the UVB radiation-induced inflammation model, only nano-based hydrogels prolonged the in vivo anti-inflammatory effect of DIM up to 48 h, indicating a prolonged effect for nanocapsules. Therefore, the nano-based hydrogels demonstrate advantageous characteristics that may enhance the effects of DIM when applied to the skin, which may be of interest in the treatment of cutaneous inflammatory disorders.