This review explores the intersection of Mpox and HIV, highlighting clinical manifestations, immune evasion mechanisms, epidemiological challenges, and prevention strategies. People with HIV (PWH), particularly those with low CD4+ cell count, face severe Mpox outcomes. Prevention relies on education, vaccination, and early detection. Integrating Mpox management into HIV care systems is vital. Since May 2022, Mpox caused by Orthopoxvirus monkeypox (MPV) Clade IIb, has affected 126 countries. In 2024, Clade Ib emerged in the Democratic Republic of Congo, leading to its declaration as a Public Health Emergency of International Concern (PHEIC). Research on MPV-HIV co-infections has provided genomic insights and protective strategies for PWH. Antivirals like tecovirimat show promise despite emerging resistance concerns. The global Mpox outbreak caused by Clade IIb and the emergence of Clade Ib underscores its growing threat. Mpox disproportionately impacts PWH, leading to severe outcomes and higher fatality rates. This review emphasizes clinical challenges, genomic advances, and prevention strategies. Enhanced surveillance, vaccination, and tailored therapies are essential to addressing this evolving health crisis.