Despite knowledge that early pubertal timing predicts adolescent girls’ substance use, it is still unclear whether this relationship persists beyond early adolescence and whether it is conditional on girls’ body weight. This study examined the moderating role of body weight in the association between early pubertal timing and adolescent girls’ substance use using three waves of data from the National Longitudinal Study of Adolescent Health. The analytic sample included 5,591 adolescent girls attending middle-schools and high-schools in the United States (ages 10–15, 71% White, 14% Black). Results indicated that early pubertal timing was associated with substance use risk but effects were attenuated after controlling for prior use. Body weight moderated the association between early pubertal timing and girls’ reported number of substances tried in middle adolescence. Body weight magnified the risk of having tried one substance, but buffered the risk of having tried three substances. Among those girls who did use substances, body weight did not moderate the relationship between early pubertal timing and heavy substance use. It is concluded that the substance use risk associated with early pubertal timing is most salient during the developmental period in adolescence when sensitivity to bodily changes may be heightened.