Introduction The IOM recommends schools adopt a Whole-of-School (WOS) approach—one that is comprehensive, coordinated, and provides opportunities for students to be active before, during, and after school. This study examined, in a nationally representative sample of secondary students in the conterminous U.S., (1) the degree of implementation of a WOS approach and (2) the association between WOS implementation and student physical activity. Methods A WOS index—based on six school practices—was calculated using self-reported school administrator data gathered in 2010 and 2011 (N=1,031). Student-level data were obtained from nationally representative samples of eighth-, tenth-, and 12th-grade students during the same years (eighth grade, nschools=96, nstudents=3,689; tenth/12th grades, nschools=178, nstudents=4,670). Multilevel Poisson models were estimated in 2013–2014 to examine the relationship between the WOS index and self-reported physical activity. Results Few students attended schools with high WOS index scores. Middle school students attending schools with higher WOS index scores were physically active for at least 60 minutes on more days than students attending schools with lower WOS index scores (exp[β]=1.031, 95% CI=1.008, 1.054). The WOS index score was not associated with physical activity among high school students. Conclusions This study finds that many schools are not offering the full array of practices comprising a WOS approach to physical activity, especially at the high school level. Yet, middle school students could have increased physical activity levels if schools were to implement a WOS approach to physical activity.