To assess the association between common polysubstance use patterns and their incremental odds for health outcomes: i) major depressive episode (MDE), ii) serious psychological distress (SPD), and iii) any mental illness (AMI). This study used data from 47,100 US adults participating in the 2022 National Survey on Drug Use and Health. Four target substance use groups: i) tobacco use only (T), ii) tobacco and alcohol (TA), iii) tobacco, alcohol, and marijuana (TAM), and iv) tobacco, alcohol, marijuana, and at least one other substance use (TAMO), were defined based on thirteen major substances to compare with no substance use. Covariate-adjusted logistic regression models were performed to assess the association with health outcomes. Tobacco use was significantly associated with a higher odds of MDE (adjusted odds ratio (aOR) = 1.32, CI = 1.04–1.66), SPD (aOR = 1.66, CI = 1.39–1.97), and AMI (aOR = 1.41, CI = 1.22–1.63). Although alcohol with tobacco does not increase the odds further, consuming marijuana as the third substance (TAM) increases the odds significantly (aORs, CIs: MDE: 2.25, 1.98–2.56, SPD: 2.28, 2.05–2.52, AMI: 2.41, 2.20–2.65). The worst outcome was observed for TAMO (aORs, CIs: MDE: 3.89, 3.40–4.46, SPD: 3.95, 3.52–4.44, AMI: 4.46, 4.00–4.99). This study showed the increased odds of MDE, SPD, and AMI for people using tobacco (T) and polysubstance, with the highest odds for the TAMO group. These findings underscore the need for targeted interventions to address tobacco and polysubstance use, as well as ongoing mental health conditions.