OBJECTIVES: Our aim was to determine the association between childhood academic ability and the onset and persistence of tobacco, alcohol and cannabis use across adolescence in a representative sample of English schools pupils. Previous research has produced conflicting findings. DESIGN: Data from 7 years of the Longitudinal Study of Young People in England (LSYPE), 2004-2010 (age 13/14-19/20). SETTING: Self-completion questionnaires during home visits, face-to-face interviews and web-based questionnaires. PARTICIPANTS: Data from 6059 participants (3093 females) with information on academic ability around age 11 and health behaviours from age 13/14 to 16/17 (early adolescence) and from age 18/19 to 19/20 (late adolescence). OUTCOME MEASURES: Regularity of cigarette smoking, alcohol drinking and cannabis use from early to late adolescence. RESULTS: In multinomial logistic regression models adjusting for a range of covariates, the high (vs low) academic ability reduced the risk of persistent cigarette smoking (RR=0.62; CI 95% 0.48 to 0.81) in early adolescence. High (vs low) academic ability increased the risk of occasional (RR=1.25; CI 95% 1.04 to 1.51) and persistent (RR=1.83; CI 95% 1.50 to 2.23) regular alcohol drinking in early adolescence and persistent (RR=2.28; CI 95% 1.84 to 2.82) but not occasional regular alcohol drinking in late adolescence. High (vs low) academic ability was also positively associated with occasional (RR=1.50; CI 95% 1.22 to 1.83) and persistent (RR=1.91; CI 95% 1.57 to 2.34) cannabis use in late adolescence. CONCLUSIONS: In a sample of over 6000 young people in England, high childhood academic at age 11 is associated with a reduced risk of cigarette smoking but an increased risk of drinking alcohol regularly and cannabis use. These associations persist into early adulthood, providing evidence against the hypothesis that high academic ability is associated with temporary ‘experimentation’ with substance use.