Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. In vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4+, CD8+, and CD3+ T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.