Thalassemias impose a substantial but highly uneven global health burden. Using Global Burden of Disease 2023 estimates, we quantified the prevalence, mortality, and disability-adjusted life years (DALYs) of thalassemias across 204 countries and territories from 1980 to 2023 and evaluated health system performance with frontier analysis. Although the global age-standardized DALY rate declined by 44.8% from 1990 to 2023, this overall reduction masks stark regional and demographic divergences. Specifically, the burden surged among women aged 20–54 years in the Caribbean and those aged >55 years in southern sub-Saharan Africa. In sharp contrast, China achieved a 78.2% reduction in age-standardized DALY rates during the same period. These divergent trajectories highlight critical gaps in global health system performance and underscore the imperative for tailored, equitable public health strategies focused on comprehensive screening, chronic disease management, and reproductive health.