Aim: The current study examined differences between individuals identifying as transgender and people identifying as cisgender in terms of (1) psychological distress (eg, anxiety, depression, and suicidal ideation), (2) rates of combustible and e-cigarette use, and (3) the potential for elevated psychological distress stemming from transgender identification to be associated with increased rates of smoking and vaping. Method: This was a secondary analysis of data from a study examining behavioral health, perceptions and behaviors associated with alcohol and other drug use, and mental health status at a large mid-western university. Differences in current use of cigarette and e-cigarette products were examined between self-identified transgender (n = 253) and cisgender (n = 18 371) respondents. Results: Overall, 17.2% (n = 2727) of the sample endorsed past 30-day use of cigarettes or e-cigarettes. Results demonstrated a significant effect of gender identity, with individuals identifying as transgender reporting higher odds of using cigarettes or e-cigarettes (AOR = 2.82, 95% CI 1.26-6.31). Regression analyses revealed significant effects of transgender identity on symptoms of anxiety ( b = 3.45, 95% CI = 1.64, 5.25, P < .001.); depression, ( b = 4.14, 95% CI = 2.21, 6.07, P < .001); and suicidal ideation, ( b = 2.51, 95% CI = 1.48, 3.55, P < .001.), respectively. Finally, we observed significant indirect effects of transgender identity on cigarette and e-cigarette product use via increased symptoms of depression (indirect effect = 0.13, 95% CI [0.07, 0.19], P < .05), and suicidal ideation (indirect effect = 0.22, 95% CI [0.15, 0.28], P < .05), but not symptoms of anxiety. Discussion: This is the first study of our knowledge to examine the association between psychological symptoms and smoking and vaping products with transgender identity. The results of this study support previous findings that transgender individuals are at risk for elevated substance use and extend the literature by demonstrating this this risk is associated with elevated psychological distress.