Background Prescription drug (PD) misuse, particularly opioid misuse, is a major US public health concern. While transgender and gender nonbinary (TGNB) individuals experience numerous health disparities, including substance use disparities, little research has focused on PD misuse in this population. Methods Data for this secondary analysis come from the US Transgender Survey (N = 26,689). First, we examined bivariate differences in past 12-month PD misuse among binary transgender women, binary transgender men, nonbinary individuals assigned-female-at-birth (AFAB), and nonbinary individuals assigned-male-at-birth (AMAB). We then used multivariable logistic regression (separately based on sex-assigned-at-birth) to examine the relationship between gender-identity related discrimination and PD misuse. Results PD misuse was significantly more common among binary transgender men (17.3 %), nonbinary AFAB individuals (18.7 %), and nonbinary AMAB individuals (18.0 %); compared to binary transgender women (13.5 %). In multivariable analyses, nonbinary identity was associated with higher odds of PD misuse among TGNB AFAB individuals (OR = 1.121; 95 %CI 1.021−1.232) and AMAB individuals (OR = 1.315; 95 % CI 1.133−1.527). Controlling for overall health status and psychological distress, public accommodations discrimination was associated with PD misuse among TGNB AMAB individuals (OR = 1.578, 95 %CI 1.354−1.839). Among both groups, healthcare discrimination was associated with PD misuse (AFAB OR = 1.388, 95 %CI 1.255−1.534; AMAB OR = 1.227, 95 %CI 1.073−1.404). Conclusion In this national sample of TGNB individuals, nonbinary individuals were at greater risk for PD misuse than binary individuals, possibly due to less societal affirmation. Similar to other TGNB health disparities, discrimination based on gender identity/expression was associated with PD misuse. This highlights the importance of interventions to reduce discrimination against TGNB individuals.