Background: Substance use disorders constitute a major public health crisis in the United States. While overall stroke mortality has declined significantly, trends in stroke mortality among individuals with documented substance use are incompletely understood across demographic and geographic strata. Objective: To compare stroke mortality trends between individuals with and without documented substance use from 1999 to 2023, and to identify demographic and geographic subgroups with elevated burden. Methods: We conducted a comparative retrospective analysis using the CDC WONDER database, examining death certificates from 1999 to 2023. Deaths were identified using ICD-10 codes for stroke and substance use. Age-adjusted mortality rates (AAMRs) per 100 000 were calculated using joinpoint regression, stratified by sex, race/ethnicity, age, census region, and urban-rural status. Results: From 1999 to 2023, stroke accounted for 4 456 273 deaths (average AAMR: 82.85 per 100 000), while stroke with documented substance use resulted in 294 474 deaths (average AAMR: 5.03 per 100 000). Overall stroke AAMR declined from 129.52 to 61.77 per 100 000 (AAPC: − 3.06%, 95% CI: − 3.66% to −2.45%, P <0.001), whereas substance-related stroke AAMR increased from 1.39 to 6.83 per 100 000 (AAPC: 6.64%, 95% CI: 4.93% to 8.38%, P <0.001). Females demonstrated steeper relative increases than males (AAPC: 8.42% vs. 6.27%), with the most dramatic acceleration among older adults ≥65 years (AAPC: 7.36%). Geographic patterns revealed highest rates in Midwest and Western states, with Oregon consistently demonstrating the highest state-level rates (14.28 per 100 000 in 2021–2023). Non-metropolitan areas experienced disproportionate burden compared to metropolitan areas (11.02 vs. 6.38 per 100 000 in 2020). Conclusions: This study identified divergent mortality trends, with declining overall stroke mortality contrasted by a nearly five-fold increase in stroke deaths with documented substance use. These patterns may reflect true epidemiological changes, improved documentation practices, or both, indicating potential for integrated surveillance and targeted interventions in high-burden populations.