Background Although there is research on the impact of social determinants of health (SDOHs) on cardiovascular health, most existing evidence is based on individual SDOH components. We evaluated the impact of cumulative SDOH burden on cardiovascular risk factors, subclinical atherosclerosis, and incident cardiovascular disease events. Methods and Results We included 6479 participants from the MESA (Multi‐Ethnic Study of Atherosclerosis). A weighted aggregate SDOH score representing the cumulative number of unfavorable SDOHs, identified from 14 components across 5 domains (economic stability, neighborhood and physical environment, community and social context, education, and health care system access) was calculated and divided into quartiles (quartile 4 being the least favorable). The impact of cumulative SDOH burden on cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, and obesity), systemic inflammation, subclinical atherosclerosis, and incident cardiovascular disease was evaluated. Increasing social disadvantage was associated with increased odds of all cardiovascular risk factors except dyslipidemia. Smoking was the risk factor most strongly associated with worse SDOH (odds ratio [OR], 2.67 for quartile 4 versus quartile 1 [95% CI, 2.13–3.34]). Participants within SDOH quartile 4 had 33% higher odds of increased high‐sensitivity C‐reactive protein (OR, 1.33 [95% CI, 1.11–1.60]) and 31% higher risk of all cardiovascular disease (hazard ratio, 1.31 [95% CI, 1.03–1.67]), yet no greater burden of subclinical atherosclerosis (OR, 1.01 [95% CI, 0.79–1.29]), when compared with those in quartile 1. Conclusions Increasing social disadvantage was associated with more prevalent cardiovascular risk factors, inflammation, and incident cardiovascular disease. These findings call for better identification of SDOHs in clinical practice and stronger measures to mitigate the higher SDOH burden among the socially disadvantaged to improve cardiovascular outcomes.