Abstract Background Physical inactivity is increasing among adolescents in the U.S., especially among girls. Despite growing evidence that parents are an important influence on adolescent health, few longitudinal studies have explored the causal relationship between parental influence and physical activity. This study examines how the relationships between parental influences and adolescent physical activity differ by gender and tests whether these relationships are mediated by adolescents' self-esteem and depression. Methods Data are from the National Longitudinal Study of Adolescent Health. The sample includes 13,246 youth, grades 7 to 12, interviewed in 1995 and again 1 year later. Logit models were used to evaluate parental influences on achieving five or more bouts of moderate to vigorous physical activity per week [MVPA] and whether the relationship between parental influence and MVPA was mediated by adolescents' level of self-esteem and depression. Results Family cohesion, parent-child communication and parental engagement positively predicted MVPA for both genders one year later (odds ratios and 95% confidence intervals for females, 1.09 [1.05–1.12], 1.13 [1.07–1.19], 1.25 [1.17–1.33] and males, 1.08 [1.04–1.11], 1.14 [1.07–1.23], 1.23 [1.14–1.33], respectively); however, parental monitoring did not (odds ratio and confidence intervals for females and males, 1.02 [.97–1.07]). For both females and males, self-esteem mediated the relationship between parental influence and physical activity. Depressive symptoms were only a mediator among males. Females reported higher levels of parent-child communication and lower family cohesion compared with males. There were no gender differences in levels of parental monitoring and engagement. Females had significantly lower levels of self-esteem and higher levels of depressive symptoms than males. Conclusion Strategies to promote physical activity among adolescents should focus on increasing levels of family cohesion, parental engagement, parent-child communication and adolescent self-esteem.