Despite extensive research, there remains a paucity of comprehensive reports on the spatiotemporal distribution, driving factors, and future trends of drug use disorders (DUDs). We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 to address this gap. In 2021, the global prevalence of DUDs reached 53,115,936 (95% UI: 46,999,805 – 60,949,054), marking a 35.50% increase since 1990 and is projected to continue rising over the next 25 years. The increment in incidence, deaths, and DALYs was 35.50%, 122.22%, and 74.65%, respectively. Despite the declining trends in global rates of incidence, prevalence, and DALYs, mortality still shows an upward trend, increasing from 1.26 to 1.65 per 100,000. Opioid and cocaine use disorders were the primary contributors to the overall increase in DUDs DALYs. Population growth was the primary driver of the increase in DUDs burden (35.31%). Health inequality regarding DUDs remain prominent issues.