PurposeWe aimed to prospectively investigate the association of an overall oxidative balance score (OBS) with all-cause death and cause-specific mortality among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of Spanish graduates.MethodsUsing baseline information on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures—vitamins C and E, β-carotenes, selenium, zinc, heme iron, polyphenols, total antioxidant capacity, body mass index, alcohol, smoking, and physical activity—we constructed an equally weighted OBS categorized into quartiles, with higher scores representing greater antioxidant balance. Cox proportional hazards models were fitted to evaluate the association between the OBS and mortality.ResultsA total of 18,561 participants (mean [SD] age, 38.5 [12.4] years; 40.8% males) were included in the analysis. During a median follow-up of 12.2 years (interquartile range 8.3–14.9), 421 deaths were identified, including 80 deaths from cardiovascular disease (CVD), 215 from cancer, and 126 from other causes. After adjustment for potential confounders, the hazard ratios and 95% confidence interval (CIs) between the highest quartile (predominance of antioxidants)vs.the lowest quartile (reference category) were 0.35 (95% CI 0.22–0.54,P-trend < 0.001) for all-cause mortality, 0.18 (95% CI 0.06–0.51,P-trend = 0.001) for CVD mortality, 0.35 (95% CI 0.19–0.65,P-trend = 0.002) for cancer mortality, and 0.45 (95% CI 0.20–1.02,P-trend = 0.054) for other-cause mortality.ConclusionOur findings suggest a strong inverse association between the OBS and all-cause, CVD, and cancer mortality. Individuals exposed to both antioxidant dietary and lifestyle factors may potentially experience the lowest mortality risk.Study registry numberDynamic Mediterranean Prospective Cohort: the SUN Project; NCT02669602.https://clinicaltrials.gov/ct2/show/NCT02669602.https://proyectosun.esSupplementary InformationThe online version contains supplementary material available at 10.1007/s00394-023-03099-8.