Background:The global epidemiology of mpox has changed substantially since its first documented human case in 1970, particularly following the multinational clade IIb outbreak in 2022 and the emergence of clade Ib since late 2023. However, temporal, regional, and clade-specific changes in the global disease burden of mpox remain incompletely characterized.Methods:We systematically searched Scopus, Web of Science, and Embase for studies published from 1970 to October 11, 2025, reporting mpox incidence, hospitalization, or case fatality, supplemented by relevant WHO reports. Meta-analysis and mixed-effects models were used to quantify disease burden and explore potential influencing factors. WHO surveillance data through November 14, 2025, were additionally analyzed to characterize temporal and regional trends.Results:Seventy studies published between 1970 and 2025 were included. Hospitalization and case-fatality rates declined from 33% and 3.3% before 2022 to 10% and 0.7% during the clade IIb–dominated global outbreak, respectively. However, clade Ia infections remained substantially more severe, with hospitalization and case-fatality rates of approximately 80% and 9%, respectively. Since 2024, Central Africa has again become a major contributor to global mpox cases and deaths, whereas high-income regions experienced larger but clinically milder outbreaks. Overall, despite global declines in disease severity, the burden of mpox remained disproportionately concentrated in Africa.Conclusions:The global burden of mpox is characterized by substantial temporal, regional, and clade-specific heterogeneity, with severe disease remaining concentrated in Africa, particularly Central Africa. Strengthened clade-specific surveillance, targeted vaccination, and enhanced health-system capacity are urgently needed in endemic regions. Future One Health approaches integrating human, animal, and environmental surveillance will be essential to improve preparedness for emerging mpox lineages and mitigate the continuing global burden of mpox.