Abstract Leveraging national data from 33 states in the U.S. for adults 18 and over (N = 347,060), from the 2020-2022 Behavioral Risk Factor Surveillance System (BRFSS), we investigated the association between current self-reported physical and mental health outcomes and substance use, focusing on alcohol, nicotine, cannabis, and all combinations of poly-substance use. Specifically, we conducted multiple weighted linear regression analyses using self-reported outcomes for poor mental and physical health in the last 30 days to examine seven mutually exclusive combinations: alcohol (A) only, nicotine (N) only, cannabis (C) only, A+N, A+C, N+C, and A+N+C. We adjusted for race, sex, age group, education level, and marital status in our analyses. For poor mental health, mean number of days ranged from 3.49 (SD = 7.07) for A-only to 10.39 (SD = 11.54) for N+C and for poor physical health, means ranged from 2.38 (SD = 6.24) to 7.17 (10.61) for N+C. All adjusted β coefficients were significant for poor mental health days, notably with the three highest being 4.36 (95%CI: 3.72-5.00) for C-only, 5.68 (95%CI: 5.06-6.30) for N+C, and 5.27 (95%CI: 4.76-5.79) for A+N+C. For poor physical health, all adjusted β coefficients were significant except for A+N, with the two highest being 2.88 (95%CI: 2.31-3.45) for C-only, 3.16 (95%CI: 2.62-3.69) for N+C, and 1.83 (95%CI: 1.54-2.11) for N-only. Recent poly-substance use containing nicotine and cannabis was both associated with 5+ days of poorer mental health and 3+ days of poorer physical health. Overall, our findings hold implications for informing future policy discourse, shaping public health campaigns, and designing educational initiatives aimed at the link between mental health and substance use. Understanding the dynamics of poly-substance use involving the three most commonly utilized substances globally among adults is critical for crafting targeted interventions. Key messages • Recent poly-substance use (alcohol, nicotine, and cannabis) is related to poorer mental and physical health in the past 30-days. • Recent nicotine and cannabis co-use is associated with 5+ days of self-reported poorer mental health and 3+ days of physical health.