<p>Loneliness is a growing public concern among emerging adults, yet little is known about its predictors in rural and reservation-based communities. This study examines whether substance use and mental health symptoms in 12th grade predict loneliness post high school among a rural reservation-based sample. Participants (<i>n</i> = 483) were surveyed in 12th grade (Spring 2024) and again six months into young adulthood (Fall 2024). Independence estimating equations with a Poisson distribution were used to assess the effect of past 30-day substance use (alcohol use, binge drinking, cannabis use, vaping cannabis, and vaping nicotine) and past 2-week mental health (anxiety and depressive symptoms) on loneliness after high school. Substance use and mental health symptoms in 12th grade were significant predictors of post high school loneliness. Alcohol use, binge drinking, cannabis use, and vaping nicotine or cannabis were each associated with a 21–24% increased risk of loneliness. Five-point increases in anxiety and depressive symptoms respectively were associated with 15% and 21% greater risk of loneliness. Prevention efforts targeting substance use and mental health before high school graduation may help reduce the risk of loneliness among rural reservation-based young people as they enter adulthood.</p>