Psoriasis is a chronic inflammatory skin disease closely related with T cells, and its management remains a challenge. Novel targets and associated drugs are urgently needed. Zeta-chain-associated protein kinase 70 kDa (ZAP-70) has been recognized as a potential target for treating autoimmune diseases due to its crucial role in T cell receptor signaling. In our previous work, we identified a potent and selective covalent ZAP-70 inhibitor with anti-inflammatory activity in vitro. Herein, we report the structural optimization of covalent ZAP-70 inhibitors. Our efforts led to the discovery of compound 25 (RDN2150), which exhibited potent inhibitory activity against ZAP-70 and favorable selectivity. It also demonstrated promising inhibitory effects on T cell activation and inflammatory cytokine production. Furthermore, a topical application of 25 resulted in significant efficacy in an imiquimod-induced psoriasis mouse model. Overall, these findings present the basis of a promising strategy for the treatment of psoriasis by targeting ZAP-70.