BACKGROUND: Monkeypox (MPOX) is a zoonotic disease caused by the MPOX virus (MPXV). MPOX resurfaced globally in May 2022, spreading throughout six WHO regions, resulting in nearly 87,000 cases and 112 deaths. Clinical symptoms include swollen lymph nodes, fever, joint pain and several neurological complications such as headache, encephalitis, myalgia, fatigue, photophobia and seizures. Despite these manifestations, the precise mechanisms of MPXV's neurotropism remain elusive. This study aimed to explore the genetic underpinnings of MPOX-related neurological manifestations, including headache, myalgia, fatigue, and photophobia, using advanced bioinformatics tools. METHODS: Data were sourced from the GeneCards database, which is an integrated database of human genes. Genes linked to MPOX and its neurological manifestations were identified and cross-referenced to uncover shared genes between these conditions. Network visualization was created using STRING, followed by topological analysis in Cytoscape to identify key genes based on degree and betweenness centrality. Functional enrichment analysis through ToppGene provided insights into molecular functions, biological processes, and cellular components associated with these target genes. Pathway analysis was performed using WikiPathways, and cell-type-specific enrichment was conducted using Enrichr. Additionally, we predicted functional microRNAs using mirTarbase and identified potential drug candidates via the Stitch database. RESULTS: We identified 32 MPOX-associated genes and a large set of neurological manifestation-related genes. Ten hub genes, including CD55, CXCL1, NFKB1, CXCL8, CD4, IL6, MX1, CFH, KLRK1, and CD46 were shared between MPOX and its neurological manifestations. Five novel genes, including CFHR3, C5AR1, C3AR1, IFNA2, and CXCL3 were predicted to be associated with MPOX and its neurological complications. Gene ontology analysis highlighted biological processes such as immune regulation, viral life cycle, and lymphocyte activation, while pathway enrichment identified critical signaling mechanisms like prostaglandin signaling, toll-like receptor 4 (TLR4) signaling, complement activation, and neuroinflammation. Moreover, cell types such as T-helper cells, natural killer cells, and microglia were found to be significantly impacted by MPOX and its frequent neurological complications. We identified 11 key microRNAs associated with MPOX-neurological manifestations and repurposed eight potential drugs, offering promising therapeutic strategies. CONCLUSION: This study emphasizes the central role of the complement system, immunological responses, and inflammatory pathways in the neurological manifestations of MPOX. The identification of novel genes and predicted therapeutic targets paves the way for future research and therapeutic interventions. Experimental validation is required to confirm these findings and determine the effectiveness of the proposed treatments.