OBJECTIVES: To test whether adolescents' mental health during the COVID-19 pandemic is associated with the combination of their instructional approach(es) and their sleep patterns. DESIGN: Cross-sectional. SETTING: Adolescents were recruited through social media outlets in October and November 2020 to complete an online survey. PARTICIPANTS: Participants were 4442 geographically and racially diverse, community-dwelling students (grades 6-12, 51% female, 36% non-White, 87% high schoolers). MEASUREMENTS: Participants completed items from the PROMIS Pediatric Depressive Symptoms and Anxiety scales. Participants reported their instructional approach(es), bedtimes, and wake times for each day in the past week. Participants were categorized into five combined instructional approach groups. Average sleep opportunity was calculated as the average time between bedtime and waketime. Social jetlag was calculated as the difference between the average sleep midpoint preceding non-scheduled and scheduled days. RESULTS: Emotional distress was elevated in this sample, with a large proportion of adolescents reporting moderate-severe (T-score ≥ 65) levels of depressive symptoms (49%) and anxiety (28%). There were significant differences between instructional approach groups, such that adolescents attending all schooldays in-person reported the lowest depressive symptom and anxiety T-scores (P < .001, η = .012), but also the shortest sleep opportunity (P < .001, η = .077) and greatest social jetlag (P < .001, η = .037) of all groups. Adolescents attending school in person, with sufficient sleep opportunity (≥8-9 hours/night) and limited social jetlag (<2 hours) had significantly lower depressive (η = .014) and anxiety (η = .008) T-scores than other adolescents. CONCLUSIONS: Prioritizing in-person education and promoting healthy sleep patterns (more sleep opportunity, more consistent sleep schedules) may help bolster adolescent mental health.