Neuropsychiatric lupus erythematosus is still a disease with a very challenging diagnostic process, lacking high specificity and sensitivity assays. Autoantibodies can change this perspective, and because of their pathogenetic involvement, can become a very powerful tool for early detection and disease activity tracking. However, their biomarker potential still needs further evaluation. In this study, we focused on the pathogenetic mechanisms of neuropsychiatric lupus erythematosus and the involvement of brain-specific and systemic autoantibodies in the development of neuropsychiatric manifestations.