Understanding youth well-being during the COVID-19 pandemic can help appropriately allocate resources and inform policies to support youth. To examine caregiver-reported changes in the psychological well-being of their children 3 to 4 months after the start of COVID-19 stay-at-home orders, and to examine the association of caregiver-reported COVID-19 exposure and family stressors with caregiver perceptions of child psychological well-being. This survey study used an anonymous survey distributed via email from June 24 to July 15, 2020, to 350 000 families of students attending public schools in Chicago, Illinois. The a priori hypotheses were that caregivers would report worsening in child psychological well-being during the closure period compared with preclosure and that exposure to COVID-19-related stressors would be associated with a higher probability of worsening child psychological well-being. Data were analyzed from September 10, 2020, to March 15, 2021. Outcomes were 7 mental health concerns and 5 positive adjustment characteristics reported by caregivers using a retrospective pre-post design. COVID-19 exposure and family stressors were also reported by caregivers. Among 350 000 families invited to participate, 32 217 caregivers (10 827 [39.3%] White, 8320 [30.2%] Latinx, 6168 [22.4%] Black; 2223 [8.1%] with multiple or other races/ethnicities) completed the survey on behalf of 49 397 children in prekindergarten through 12th grade. Child-specific outcomes were reported for 40 723 to 40 852 children depending on the specific question. The frequency of caregiver endorsement of youth mental health concerns ranged from 0.1 percentage point (suicidal ideation or self-harm, reported by 191 caregivers [0.5%] preclosure vs 246 caregivers [0.6%] during closure; P < .001) to 28.3 percentage points (loneliness, reported by 1452 caregivers [3.6%] preclosure vs 13 019 caregivers [31.9%] during closure; P < .001) higher after the end of in-person instruction compared with preclosure. Frequency of caregiver endorsement of youth positive adjustment characteristics ranged from -13.4 percentage points (plans for the future, reported by 18 114 caregivers [44.3%] preclosure vs 12 601 caregivers [30.9%] during closure; P < .001) to -30.9 percentage points (positive peer relationships, reported by 24 666 caregivers [60.4%] preclosure vs 19 130 caregivers [46.8%] during closure; P < .001) lower after the end of in-person instruction. Significant differences in COVID-19 exposure were observed across racial/ethnic (F3,27 534 = 614.8; P < .001) and household income strata (F5,27 506 = 842.0; P < .001). After accounting for covariates, all mental health concerns increased in probability (eg, angry: odds ratio, 1.55 [95% CI, 1.48-1.62]; P < .001) and all the positive adjustment characteristics decreased in probability (eg, hopeful or positive: odds ratio, 0.88 [95% CI, 0.84-0.92]; P < .001) as COVID-19 exposure and family stressors increased. In this survey study of caregivers during the COVID-19 pandemic, COVID-19 and resulting exposure to stress were associated with worse youth psychological well-being, demonstrating the need for a comprehensive public health approach that prioritizes children's well-being and draws broad public attention to the mental health needs of youth.