Previous studies have documented associations between perceptions of racial/ethnic discrimination and adverse health outcomes among Hispanics and other minority groups. However, these studies have not examined change in perceived discrimination over the lifecourse and whether trajectories of perceived discrimination affect outcomes differently. This study of 2722 Hispanic students identified trajectories of perceived discrimination from 9th grade through emerging adulthood (approximately ages 14–23), and compared these trajectory groups on substance use outcomes. Four distinct trajectory groups were identified: (1) low and stable discrimination, (2) increasing discrimination, (3) initially high but decreasing discrimination, and (4) high and stable discrimination. Compared with the low and stable discrimination group, the groups that experienced higher levels of discrimination were at higher risk of cigarette, alcohol, marijuana, and hard drug use. Specifically, the group with increasing discrimination (group 2) had a higher risk of alcohol, marijuana, and hard drug use; the group with initially high but decreasing discrimination (group 3) had a higher risk of cigarette smoking and alcohol use; and the group with high and stable discrimination (group 4) had a higher risk of alcohol, marijuana, and hard drug use. Results indicate that experiencing discrimination during adolescence, emerging adulthood, or both, regardless of whether the discrimination increases or decreases, could place Hispanic youth at risk for substance use. Health education programs are needed to help Hispanic youth learn effective skills to cope with discrimination without resorting to substance use.