Transgender individuals experience numerous health disparities relative to cisgender individuals. However, most transgender-health studies have focused on convenience samples with limited generalizability. This study utilized data from the 2016-2018 TransPop Study, the first national probability sample of transgender adults (n=274) with a cisgender comparison sample (n=1162). Using multivariable logistic regression, adjusted for demographics, we compared the prevalence of hazardous drinking, problematic drug use, serious psychological distress, suicidality, and non-suicidal self-injury between transgender and cisgender individuals and among transgender men (n=78), transgender women (n=120), and transgender nonbinary individuals (n=76). Among transgender individuals, 28.2% (95%CI 21.2-35.2) and 31.2% (95%CI 23.8-38.7) reported hazardous drinking and problematic drug use, respectively; 44.4% (95% CI 35.8-53.0) reported recent suicidal ideation, 6.9% (95% CI 2.3-11.5) reported a recent suicide attempt, and 21.4% (95% CI 14.5%-28.4%) reported recent non-suicidal self-injury. In their lifetime, 81.3% (95%CI 75.1-87.5) of transgender respondents had suicidal ideation, 42.0% (95%CI 34.2-49.8) had attempted suicide, and 56.0% (95% CI 48.2-63.8) reported non-suicidal self-injury. Most (81.5%; 95%CI 75.5-87.5) had utilized formal mental health care and 25.5% (95%CI 18.5-32.4) had sought informal mental health support. There were no differences in alcohol or drug-use outcomes between transgender and cisgender adults. Compared to cisgender adults, transgender adults had higher odds of serious psychological distress (aOR=3.1; 95%CI 1.7-5.7), suicidal ideation (recent: aOR=5.1, 95%CI 2.7-9.6); lifetime: aOR=6.7, 95%CI 3.8-11.7), lifetime suicide attempts (aOR=4.4, 95%CI 2.4-8.0), and non-suicidal self-injury (recent: aOR=13.0, 95%CI 4.8-35.1); lifetime: aOR=7.6, 95%CI 4.1-14.3). Transgender nonbinary adults had the highest odds for all outcomes, including substance use outcomes. Findings from these national probability samples support those of earlier convenience-sample studies showing mental health disparities among transgender adults relative to cisgender adults, with nonbinary individuals at highest risk. These findings also highlight variations in risk across sub-groups of transgender individuals.