<p>A comprehensive analysis of the global burden and trends of mental disorders (MDs) and substance use disorders (SUDs) among reproductive-age women is lacking. This study estimated the burden of disease attributable to MDs and SUDs in reproductive-age women from 1990 to 2021. Using data from the Global Burden of Disease Study 2021, we assessed the prevalence, incidence, and years lived with disability (YLDs) of 12 types of MDs and SUDs among reproductive-age women between 1990 and 2021. Estimates were stratified by age and sex at global, regional, and national levels. Trends were evaluated using the average annual percentage change (AAPC) and total percentage change. In 2021, the global age-standardized prevalence rates per 100,000 population among reproductive-age women were 17,573 (95% uncertainty interval 15,443–19,954) for MDs and 1806 (95% uncertainty interval 484–2191) for SUDs. Among MDs, depressive and anxiety disorders were the leading contributors to YLDs, with age-standardized YLD rates of 1,073.5 (686.73–1,562.48) and 844.05 (532.79–1,232.57) per 100,000 population, respectively. From 1990 to 2021, age-standardized rates of the prevalence, incidence, and YLDs of MDs increased (AAPC: 35%, 55%, and 38%, respectively), while those of SUDs decreased (AAPC: −55%, −62%, and −19%, respectively). The burden of both MDs and SUDs was highest in regions with higher sociodemographic indices. The greatest increases in burden were observed among younger women aged 15–24 years with MDs and 15–34 years with SUDs. MDs and SUDs are substantial contributors to the global disease burden in reproductive-age women. The magnitude and distribution of this burden vary by disorder type, country, age group, and sociodemographic development.</p>