BackgroundPrevious research has demonstrated a significant association between vision and/or hearing loss and lifetime substance use. ObjectiveThe objective of this analysis was to assess whether depression mediates the association between vision and/or hearing loss and recent substance use (RSU). MethodsData from 9408 NHANES 2013–2018 participants were used for a survey-weighted analysis to assess whether the indirect effect (IE) of disability status (neither, vision loss only, hearing loss only, both) on the outcome RSU (past 30-day use of marijuana, cocaine, methamphetamine, or heroin) was mediated by recent (past 2 weeks) depression (Patient Health Questionnaire- 9 items score; none = 0–4, mild or greater = 5+), adjusting for confounders. ResultsThe estimated prevalence of vision and/or hearing loss, mild or greater depression, and RSU were 6.7 %, 24.1 %, and 16.8 %. RSU was significantly positively associated with disability status before (p = .018) but not after adjusting for depression (p = .160), and the indirect effects were statistically significant (p < .001). ConclusionsThe data are consistent with the hypothesis that recent depression mediates the association between vision and/or hearing loss and RSU. Initiatives may be needed that incorporate a focus on the prevention, management, or care for depression to intervene on the pathway between hearing and/or vision loss and RSU.