An individual’s age at first substance use may be associated with their risk for progression toward heavier substance involvement. To our knowledge, however, no studies within nationally representative samples have examined the relation between the timing of initiation and progression in use of multiple substances. The present study employed a sample of 9,421 participants from the National Longitudinal Study of Adolescent to Adult Health who reported on their ages of tobacco, alcohol, and cannabis initiation; frequency of tobacco, alcohol, and cannabis use; and quantity of tobacco and alcohol use across 4 waves. We fit latent growth models to examine (a) associations between the age of initiation and initial status and rate of change in substance involvement, and (b) the degree to which the timing of first substance use accounted for differences in trajectories. There were significant relations between all ages of initiation and rates of change in tobacco (βs = −0.21 to −0.31, ps < .01) and alcohol use frequency (βs = 0.14 to 0.31, ps < .001), age of cannabis initiation and rate of change in tobacco use quantity (β = 0.23, p < .01), and age of tobacco initiation and rate of change in cannabis use frequency (β = −0.14, p < .01). After adjusting for age of initiation, significant associations were observed between trajectories for tobacco and alcohol (r = .43, p < .0001) and alcohol and cannabis (r = .20, p < .05). Results highlight differences in within- and cross-substance relations between the age of initiation and rate of change in use across substances. They suggest that differences in substance use trajectories are partly accounted for by age at first use.