Cutaneous fungal infections are frequently associated with an inflammatory component including irritated skin, itching and stinging/burning. Therapeutic anti-fungal agents that have anti-inflammatory activity have the potential to provide clinical benefit beyond fungus eradication. Recently, certain anti-fungal agents have been shown to have intrinsic anti-inflammatory activity, therefore we sought to determine the extent of the anti-inflammatory activity of these compounds. The anti-inflammatory activities of eight anti-fungal agents (butoconazole, ciclopirox olamine, fluconazole, miconazole nitrate, sertaconazole nitrate, terconazole, tioconazole and ketoconazole) were compared in a number of preclinical models of dermal inflammation and pruritus. While butoconazole, ciclopirox olamine, fluconazole, and miconazole nitrate were all found to have anti-inflammatory activity, only sertaconazole nitrate reduced the release of cytokines from activated lymphocytes and mitigated inflammation in animal models of irritant contact dermatitis and neurogenic inflammation. In addition, sertaconazole nitrate inhibited contact hypersensitivity and scratching responses in a murine model of pruritus. Furthermore, the in vitro and in vivo anti-inflammatory activity of sertaconazole nitrate was found to be greater than other topical anti-fungal agents examined. These studies demonstrate that topical administration of clinically relevant concentrations of sertaconazole nitrate resulted in an efficacious anti-inflammatory activity against a broad spectrum of dermal inflammation models and itch. The anti-inflammatory properties of sertaconazole may contribute to the efficacy of the drug in the treatment of cutaneous fungal conditions and provide greater anti-inflammatory activity compared with other anti-fungal agents.