Purpose <p>To examine the relationship between residential racial and economic segregation and main causes of death at the county level in the USA.</p> Methods <p>Residential racial and economic segregation quintiles were determined using the Index of Concentration at the Extremes (ICE). Linear mixed-effects model was applied to calculate adjusted mortality rate ratios (aRR).</p> Results <p>The ICE for race + income outperformed the ICE for race and the ICE for income. Among 3142 counties, the average age-adjusted all-cause mortality rates were 980.25, 919.82, 844.37, 781.82, and 703.01 per 100,000 across ICE for&#xa0;race + income quintiles, from the most deprived to the most privileged, respectively (<i>p</i> for trend: &lt; 0.001). The corresponding aRRs for all-cause mortality were 1.32, 1.23, 1.17, 1.10, and 1 (<i>p</i> for trend: &lt; 0.001). Furthermore, both mortality rates and aRRs for all 11 main causes of death showed a significant decrease from the most deprived to the most privileged counties (<i>p</i> for trend: &lt; 0.001).</p> Conclusions <p>There is a strong association between residential racial and economic segregation and age-adjusted all-cause mortality as well as the 11 main causes of death in US counties, with a clear decreasing trend observed across ICE for race + income quintiles. These findings underscore the urgent need for policy interventions to reduce residential segregation, including equitable urban planning, investment in underserved communities, and improved access to healthcare and education in disadvantaged areas. Addressing these structural inequities could be an effective strategy for reducing mortality disparities and advancing health equity.</p>