Previous research suggests that sexual minority youth have poorer health-related outcomes than their heterosexual peers. The purpose of this study is to determine whether sexual orientation disparities in mental health and substance use increase, decrease, or remain the same during the transition from adolescence to adulthood. Data are from Waves 1-4 of the National Longitudinal Study of Adolescent Health (n = 8,322; 55% female). Respondents were in grades 7-12 at Wave 1 and aged 24-32 at Wave 4. Latent growth curve modeling is used to compare the mental health and substance use trajectories of youth who consistently report heterosexual attraction versus those who consistently report lesbian, gay, or bisexual (LGB) attraction, those who report a transition to LGB attraction, and those who report a transition to heterosexual attraction. Among women and men, sexual orientation disparities in depressive symptoms and suicidal thoughts persist, but do not increase, during the transition from adolescence to adulthood. The same pattern is observed for disparities in smoking, heavy drinking, and marijuana use among women. Among men, disparities in substance use are only observed between those who report consistent heterosexual attraction and those who transition to heterosexual attraction. Disparities between these groups persist over time for heavy drinking and marijuana use but decrease over time for smoking. While this study finds evidence of numerous disparities in mental health and substance use outcomes during adolescence and young adulthood, particularly among young women, there is no indication that these disparities get larger over time.