This study explored sexual orientation and gender identity as predictors of health literacy among adolescents attending New York City (NYC) public high schools. Many studies have demonstrated disparities in sexual health among sexual and gender minority (SGM) adolescents. However, little is known about their health literacy. Health literacy, defined as the capacity to acquire, understand, appraise, and apply health information, especially in health decision-making, is a known predictor of health. Data came from a quantitative cross-sectional survey (N = 1,438) collected at 15 high schools in the Bronx, NYC. Four aspects of health literacy were explored: (1) knowledge of sexually transmitted infections (STIs), (2) knowledge of sexual health rights in New York State, (3) health access literacy and self-efficacy, and (4) health communication. Linear regression analysis was used to test predictors of health literacy. Contrary to our hypothesis, SGM adolescents did not score significantly lower on the health literacy variables compared with cisgender heterosexual adolescents. SGM adolescents scored significantly higher on knowledge of STIs and knowledge of health rights compared with cisgender heterosexual young men. Adolescents who were questioning their sexual identity scored significantly lower compared with both SGM and cisgender heterosexual adolescents on all four health literacy scales. Interventions are needed to ensure that in-school curricula are inclusive and address health literacy among questioning adolescents and cisgender heterosexual young men. Addressing the health needs of questioning adolescents is particularly important because adolescence is a critical time of decision-making around sexuality and health.