Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of subtypes with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and resident microglia) are also important facilitators of NPSLE. An improving understanding of NPSLE may provide further options for managing this disease. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for novel targeted therapies. Conventional therapeutic algorithms include symptomatic, anti-thrombotic, and immunosuppressive agents that are only supported by observational cohort studies, therefore performing controlled clinical trials to guide further management is essential and urgent. In this review, we aimed to present the latest pathogenetic mechanisms of NPSLE and discuss the progress in its management.