Psoriasis is an auto-immune disease resulting from a chronic and exaggerated inflammation of the skin and hyperproliferation of keratinocytes. Conventional topical treatments for this disease, such as anti-inflammatory drugs, present low efficiency, and systemic administration of synthetic drugs or biologic immunomodulators can present severe side effects and/or are highly expensive. So, there is an unmet need to develop new drugs that could provide sustainable therapeutic effects. In this study, we evaluated the potential efficacy of anti-inflammatory dendrimers for the topical treatment of psoriasis. Dendrimers are hyperbranched and perfectly defined macromolecules of nanometer size, constituted of branches grafted on a central core. IMD-006, a phosphorus-based dendrimer capped with azabisphosphonate groups, has strong immuno-modulatory effects towards different immune cell types. We tested the effects of IMD-006 in two psoriasis models: the imiquimod- induced murine model and a reconstructed human epidermis (RHE) model, in which cocktails of pro-inflammatory cytokines are used to induce psoriasis-associated changes. IMD-006 presented dose-dependent therapeutic efficacies, significantly reducing lesions and histopathological changes associated with psoriasis. Moreover, we show that IMD-006 is rapidly taken up by kerati- nocytes in 2D culture, decreasing their proliferation and increasing their differentiation. In keratinocytes in 2D culture, IMD-006 associated with mitochondria, increased mitochondrial ROS production and ultimately lysosomal degradation of these organelles. Therefore, the anti-psoriatic effect of dendrimers is, at least in part, the result of a direct effect on keratinocytes. Our results demonstrate that anti-inflammatory dendrimers are good candidates for the topical treatment of psoriasis with a broad effect on multiple cell types involved in the development and progression of the disease.