BACKGROUND: Monkeypox virus (MPXV) has emerged as a significant global health concern with outbreaks worldwide. While MPXV is primarily known for its dermatological and systemic manifestations, it can also cause central nervous system (CNS) complications. This systematic review describes the demographic, clinical, diagnostic, and therapeutic characteristics of MPXV-associated CNS neuroinflammatory disorders. METHODS: We systematically reviewed the literature to identify cases of MPXV-associated CNS neuroinflammatory disorders. Data on demographics, systemic and neurological manifestations, diagnostic methods, treatment strategies, and outcomes were extracted and analyzed. RESULTS: Eighteen cases of MPXV-associated neuroinflammatory disorders were identified. The mean age of patients was 27.8 years (range: 28 days to 43 years), with a male predominance (66.7%). Diagnosis included The most common diagnoses were acute disseminated encephalomyelitis in nine cases (50.0%), encephalitis/meningoencephalitis in seven cases (38.9%, isolated transverse myelitis in one case (5.6%), and transverse myelitis with encephalitis in one case (5.6%). The latency between the onset of systemic symptoms and neurological involvement averaged 6.2 days. MPXV detection was confirmed in 13 of 18 (72.2%) cases, primarily using quantitative real-time polymerase chain reaction from various biological specimens. Among the 12 cases with documented treatment, the most commonly administered therapies were tecovirimat (58.3%) and intravenous methyl-prednisolone (66.7%). Outcomes were reported in 17 cases, with complete recovery in 29.4%, partial recovery in 41.2%, and death in 29.4% of patients. CONCLUSIONS: MPXV-associated neuroinflammatory disorders of the CNS are rare but cause significant complications. The findings underscore the need for clinical vigilance, advanced diagnostic approaches, and targeted therapeutic strategies. Further research is essential to elucidate mechanisms underlying MPXV neurovirulence and develop effective treatments for these life-threatening conditions.