Outcome expectancies have been found to be predictive of substance use. While development of expectancies may be dynamic during adolescence, it is unknown whether the rate of change (slope) in substance use expectancies is a risk factor for use onset across multiple substance use domains. The present study tested the hypothesis that the slope of positive and negative alcohol, tobacco, and marijuana use expectancies during mid-adolescence (9th-10th grade) would predict use onset of each respective substance during late adolescence (11th-12th grade). Data from 3,396 ethnically diverse high school students were collected across eight waves of assessment and analyzed within a latent growth modeling framework. Results revealed that the slopes of positive substance use expectancies among never-users of each respective substance predicted increased odds of onset (Alcohol: ORB = 7.73, p < .001; Tobacco: ORB = 5.58, p < .001; Marijuana: ORB = 2.49, p = .001). Only the slope of negative marijuana expectancies predicted increased odds of onset (Marijuana: ORB = .44, p = .04). Baseline level of positive and negative substance use outcome expectancies were also generally found to be associated with onset. For three common drugs used by adolescents, change in substance use expectancies during the first two years of high school may be a marker of risk propensity for substance use onset. Change in expectancies may be an important target in substance use prevention, with research indicating that expectancy challenge and life skills interventions being potentially efficacious.