Background <p>Although studies have shown that poor sleep health, depressive symptoms, and substance use are independent predictors of poor cardiovascular health, it is unclear how these factors combine during adolescence to affect cardiovascular health later in life. We therefore examined the impact of poor sleep health, depressive symptoms, and substance use during adolescence on future CVD risk.</p> Methods <p>We conducted a secondary analysis using Waves I, II, and IV of the Add Health dataset. The primary exposure variable (sleep health) was derived from three sleep factors (sleep duration, bedtime, and insomnia) measured at Wave (I) Depressive symptoms were assessed at Wave II using the Center for Epidemiological Studies Depression Scale (CES-D). A combined measure of substance use was developed based on self-reported smoking status, binge drinking, and marijuana use at Wave (II). We estimated the controlled direct effect of adolescent poor sleep health on future cardiovascular disease risk mediated through depressive symptoms and substance use using marginal structural models.</p> Results <p>Approximately 61% of study participants (<i>n</i> = 1,942) experienced poor sleep health. The prevalence of depressive symptoms and substance use was 7.8% and 25%, respectively. Adolescents with poor sleep health who also used substances had a significantly higher CVD risk in adulthood (OR: 1.83, 95% CI: 1.28, 2.64) compared to those with poor sleep health who did not use substances.</p> Conclusion <p>Adolescents with poor sleep health who use substances face a higher risk of CVD in adulthood. Future efforts to reduce CVD risk should focus on adolescents with sleep and substance use issues.</p>