Background <p>Hyperuricemia is associated with higher all-cause and cardiovascular mortality. However, the role of social determinants of health (SDoH) in this context remains unclear. This study aims to examine the relationship between SDoH, hyperuricemia, all-cause and cardiovascular mortality, and explore the mediating role of SDoH in these relationships.</p> Methods <p>This cohort study analyzed data from 23,919 US adults (aged ≥ 20) in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016, with linked mortality data through December 31, 2019. Two primary exposures were examined: hyperuricemia, defined as serum uric acid level &gt; 420&#xa0;µmol/L in males and &gt; 360&#xa0;µmol/L in females, and SDoH, which encompassed education level, marital status, income-to-poverty ratio (PIR), food security, health insurance, regular health-care access, housing instability, and employment. The primary outcomes were all-cause and cardiovascular mortality. Statistical methods included logistic regression, Cox proportional hazard model, and mediation analysis.</p> Results <p>The study cohort had a mean (SD) age of 49.27 (17.63) years, with 48.28% (95%Cl, 47.69%-48.86%) being male, and 68.52% (95%Cl, 65.27%-71.60%) identified as non-Hispanic White. Having three or more unfavorable SDoH significantly mediated the link between hyperuricemia and both all-cause and cardiovascular mortality. SDoH ≥ 6, SDoH = 5, SDoH = 4, and SDoH = 3 mediated 20.30% (<i>P</i> = 0.004), 13.94% (<i>P</i> = 0.044), 23.59% (<i>P</i> = 0.018), and 13.88% (<i>P</i> = 0.008) of the association between hyperuricemia and all-cause mortality, respectively. SDoH ≥ 6, SDoH = 5, SDoH = 4, and SDoH = 3 mediated 15.35% (<i>P</i> = 0.006), 14.87% (<i>P</i> = 0.050), 20.68% (<i>P</i> = 0.026), and 9.45% (<i>P</i> = 0.012) of the association between hyperuricemia and cardiovascular mortality.</p> Conclusions <p>SDoH significantly mediated the relationship between hyperuricemia and both all-cause and cardiovascular mortality.</p>