This study investigated the potential association between uranium exposure and mortality from cerebrovascular diseases, with a focus on the mediating effects of lipid indicators. Employing recommended sampling weights to account for National Health and Nutrition Examination Survey’ complex survey design, this analysis drew from data collected between 2005 and 2016. The study examined the impact of uranium on mortality from cerebrovascular diseases using various statistical approaches, including Cox regression to assess linear relationships within metal mixtures. It also evaluated the role of lipid-adjusted plutonium (LAP) as a mediator and verified the persistence of associations across different subgroups. The study encompassed 4312 participants and established a significant direct link between uranium levels and mortality from cerebrovascular diseases (hazard ratio (95%CI) = 20.4243 (20.1347–20.7181), P = .0266). It also identified LAP as a mediating factor in the relationship, accounting for a mediated proportion of 1.35%. The findings highlight a pivotal connection between uranium exposure and increased mortality due to cerebrovascular diseases, with LAP playing a significant intermediary role.