Delaying high school start times prolongs weekday sleep. However, it is not clear if longer sleep reduces depression symptoms and if the impact of such policy change is the same across groups of adolescents. We examined how gains in weekday sleep impact depression symptoms in 2,134 high school students (mean age 15.16 ± 0.35 years) from the Minneapolis metropolitan area. Leveraging a natural experiment design, we used the policy change to delay school start times as an instrument to estimate the effect of a sustained gain in weekday sleep on repeatedly measured Kandel-Davies depression symptoms. We also evaluated whether allocating the policy change to subgroups with expected benefit could improve the impact of the policy. Over 2 years, a sustained half-hour gain in weekday sleep expected as a result of the policy change to delay start times decreased depression symptoms by 0.78 points, 95%CI (-1.32,-0.28), or 15.6% of a standard deviation. The benefit was driven by a decrease in fatigue and sleep-related symptoms. While symptoms of low mood, hopelessness, and worry were not affected by the policy on average, older students with greater daily screen use and higher BMI experienced greater improvements in mood symptoms than would be expected on average, signaling heterogeneity. Nevertheless, universal implementation outperformed prescriptive strategies. High school start time delays are likely to universally decrease fatigue and overall depression symptoms in adolescents. Students who benefit most with respect to mood are older, spend more time on screens and have higher BMI.