Objective <p>To investigate the separate, joint, as well as interactive associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations and oxidative balance score (OBS) with mortality among individuals with metabolic syndrome (MetS).</p> Methods <p>The analysis included 12,078 participants with MetS from the National Health and Nutrition Examination Survey (NHANES) 2001–2018. Mortality was ascertained by linkage to National Death Index records through 31 December 2019.</p> Results <p>During 99,690 person-years of follow-up, 2357 deaths were documented, including 654 cardiovascular disease (CVD) deaths and 518 cancer deaths. A pronounced “L-shaped” nonlinear relationship was observed between 25(OH)D and mortality; the hazard ratio (HR) [95% confidence interval (CI)] for 25(OH)D ≥ 75.0 vs. &lt; 50.0 nmol/L (reference) were 0.71 (0.61, 0.82), 0.65 (0.48, 0.86), and 0.77 (0.57, 1.05) for all-cause, CVD, and cancer mortality, respectively. A reverse linear relationship was demonstrated between OBS and mortality; the HRs (95% CI) for high OBS vs. low OBS (reference) were 0.76 (0.68, 0.86), 0.70 (0.58, 0.85), and 0.75 (0.60, 0.94) for all-cause, CVD, and cancer mortality, respectively. In the joint analyses, the combination of 25(OH)D ≥ 75.0 nmol/L and high OBS was associated with the lowest risk of all-cause (HR 0.57, 0.46–0.70) and CVD mortality (HR 0.48, 0.34–0.69). In contrast, participants with 25(OH)D levels of 50.0-74.9 nmol/L and high OBS presented the lowest risk of cancer mortality (HR 0.52, 0.34–0.81). A significant synergistic additive interaction between OBS and sufficient 25(OH)D levels on CVD mortality was observed [relative excess risk due to interaction (RERI) = 0.29, 95% CI: 0.02–0.57], with 47% of the total protective effect attributable to their interaction.</p> Conclusions <p>Adequate 25(OH)D and higher OBS are significantly associated with lower risk of mortality and exhibit enhanced protective effects on CVD mortality risk.</p> Graphical abstract <p></p>