: infection (CDI) is a major cause of healthcare-associated infections globally. Understanding variations in CDI incidence and outcomes across settings, populations, and regions is important for guiding prevention strategies. : The aim of this study was to determine the global epidemiology of CDI to better understand disease burden across settings and geographic regions. : Relevant publications were identified through searches of major databases, including PubMed, Scopus, and Web of Science, published from 1 January 2016 through 24 July 2024. Random effects models were used to pool estimates, and 95% confidence intervals (CIs) were calculated. : A total of 59 studies, representing 24 countries across North America, Europe, the Asia-Pacific region, Latin America, and the Middle East, met the inclusion criteria. The incidence of CDI was highest in hospital-onset healthcare facility settings, with 5.31 cases/1000 admissions (95% CI 3.76-7.12) and 5.00 cases/10,000 patient-days (95% CI 3.96-6.15). Long-term care facilities reported 44.24 cases/10,000 patient-days (95% CI 39.57-49.17). Pediatric populations faced a greater risk, with 4.52 cases/1000 admissions (95% CI 0.55-12.17), than adults did at 2.13 (95% CI 1.69-2.61). Recurrence rates were highest for community-acquired CDI at 16.22%. The death rates for the CDI cases tracked for 30 days and of unspecified duration were 8.32% and 16.05%, respectively. : This comprehensive review identified healthcare facilities, long-term care, pediatric populations, and North America as disproportionately burdened. This finding provides guidance on priority areas and populations for targeted prevention through antimicrobial stewardship, infection control, and surveillance.