Background There are limited data on substance use (SU) and cardiovascular disease (CVD)–related mortality trends in the United States. We aimed to evaluate SU+CVD–related deaths in the United States using the Centers for Disease Control and Prevention Wide‐Ranging, Online Data for Epidemiologic Research database. Methods and Results The Multiple Cause‐of‐Death Public Use record death certificates were used to identify deaths related to both SU and CVD. Crude, age‐adjusted mortality rates, annual percent change, and average annual percent changes with a 95% CI were analyzed. Between 1999 and 2019, there were 636 572 SU+CVD‐related deaths (75.6% men, 70.6% non‐Hispanic White individuals, 65% related to alcohol). Age‐adjusted mortality rates per 100 000 population were pronounced in men (22.5 [95% CI, 22.6–22.6]), American Indian or Alaska Native individuals (37.7 [95% CI, 37.0–38.4]), nonmetropolitan/rural areas (15.2 [95% CI, 15.1–15.3]), and alcohol‐related death (9.09 [95% CI, 9.07 to 9.12]). The overall SU+CVD‐related age‐adjusted mortality rates increased from 9.9 (95% CI, 9.8–10.1) in 1999 to 21.4 (95% CI, 21.2–21.6) in 2019 with an average annual percent change of 4.0 (95% CI, 3.7–4.3). Increases in SU+CVD‐related average annual percent change were noted across all subgroups and were pronounced among women (4.8% [95% CI, 4.5–5.1]), American Indian or Alaska Native individuals, younger individuals, nonmetropolitan areas, and cannabis and psychostimulant users. Conclusions There was a prominent increase in SU+CVD‐related mortality in the United States between 1999 and 2019. Women, non‐Hispanic American Indian or Alaska Native individuals, younger individuals, nonmetropolitan area residents, and users of cannabis and psychostimulants had pronounced increases in SU+CVD mortality.