Psoriasis is a chronic inflammatory dermatological disorder characterized by the aberrant differentiation and hyperproliferation of epidermal keratinocytes, boosted immune cell infiltration, and cytokine and chemokine production. Patients with psoriasis experience persistent discomfort and their conditions remain incurable. Therefore, development of safe and effective treatments for psoriasis is critical. Amlexanox, a tricyclic amine carboxylic acid, has various pharmacological advantages in previous studies, including anti-inflammatory, anti-allergic, immunomodulatory, and metabolic properties. Here we used the imiquimod (IMQ)-induced animal model and interleukin 17 A (IL-17A) activated keratinocytes to examine the efficacy of amlexanox in the treatment of psoriasis. Immunological and histological analyses revealed that both topical and oral administration of amlexanox reduced psoriatic symptoms such as increased skin thickness, erythema, scale formation, and immune cell infiltration. In the IMQ-induced mouse model, amlexanox also reduced splenic Th17 cell counts and the production of IL-17/Th17-associated cytokines and chemokines. Furthermore, amlexanox inhibited nuclear factor-κB phosphorylation in IL-17 activated keratinocytes. These findings indicated that amlexanox effectively alleviated psoriatic symptoms through both oral and topical administration. We propose that amlexanox is a potent therapeutic candidate for the treatment of psoriasis.