Psoriasis is a common chronic immune-mediated skin disease characterized by hyperproliferation and aberrant differentiation of keratinocytes and massive infiltration of inflammatory immune cells. Recent studies showed that Signal Transducer and Activator of Transcription 3 (STAT3), which plays an important role in cell survival, proliferation, differentiation, angiogenesis, and immune responses, is constitutively activated in epidermal keratinocytes of human psoriatic skin lesions. In addition, STAT3 promotes the differentiation and expansion of T cells and facilitates cytokine production, thereby exacerbating the condition of psoriasis. Alantolactone (ALT) is a sesquiterpene lactone compound that could selectively suppress STAT3 activation, but its effectiveness and application in psoriasis treatment have not been determined. In this study, we developed ALT loaded chitosan/hyaluronic acid nanoparticles (CHALT), and investigated its therapeutic potential for psoriasis therapy. CHALT effectively abrogated the hyperproliferation by inducing ROS-mediated apoptosis with loss of mitochondrial membrane potential, and also inhibited IL-6-induced STAT3 signaling activation and inflammatory reaction in HaCaT cell line. In an Imiquimod (IMQ)-induced psoriasis model, the topical treatment of psoriasis lesions with CHALT effectively attenuated the STAT3 hyperactivation within keratinocytes and ameliorated the symptoms of psoriasis. In addition, it was found that CHALT restricted the recruitment of immune cells. These results indicated that ALT-based nanoformulation CHALT holds great potential for psoriasis therapy.