Psoriasis is a prevalent chronic inflammatory skin disease characterized by thickening of the epidermis accompanied by lesional erythema, scaling, and induration as a result of abnormal proliferation of keratinocytes. During the development of psoriasis, levels of intracellular reactive oxygen species (ROS) within psoriatic lesions are elevated, activating a pro-inflammatory signaling cascade. Here, we evaluated the therapeutic efficacy and mode of action of bilirubin nanoparticles (BRNPs), based on the potent, endogenous antioxidant bilirubin, in a preclinical psoriasis model. We found that topical treatment of psoriatic lesions with BRNPs effectively attenuated upregulation of intracellular ROS levels within keratinocytes and ameliorated the symptoms of psoriasis. A subsequent mechanistic study showed that preventing oxidative stress in activated keratinocytes suppressed the secretion of inflammatory mediators and recruitment of immune cells. Subsequent expression of the antigen-presenting cell (APC) maturation markers, class II major histocompatibility complex (MHC class II), cluster of differentiation (CD) 80 and CD86, was significantly decreased, resulting in a reduction in the differentiation of naive CD4(+) T cells into interleukin (IL)-17-producing T-helper (Th) 17 cells. Unlike the commercial corticosteroid drug, clobetasol propionate (CLQ), BRNPs, composed of the endogenous antioxidant bilirubin and the approved polymer polyethylene glycol (PEG), did not exert systemic cytotoxicity. Collectively, these findings highlight the potential of BRNPs as a novel nanomedicine for ameliorating psoriasis-like skin inflammation through topical treatment and suggest that their use could be further expanded to treat other chronic skin inflammation diseases, including atopic dermatitis.