Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.