IMPORTANCEImpacts of COVID-19 on reservation-area American Indian youth are unknown and may be substantial owing to the significant COVID-19 morbidity and mortality experienced by American Indian populations. OBJECTIVE To measure self-reported illness experiences and changes in psychosocial factors during the COVID-19 pandemic among reservation-area American Indian youth. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included a random sample of US schools on or near US Indian reservations during Spring 2021, stratified by region, with students in grades 6 to 12 completing cross-sectional online surveys. All enrolled self-identifying American Indian students in grades 6 to 12 attending the 20 participating schools were eligible to be surveyed; participants represented 60.4% of eligible students in these schools. Data were analyzed from January 5 to July 15, 2022. EXPOSURES Onset of the COVID-19 pandemic. MAIN OUTCOMES AND MEASURES Outcomes of interest were COVID-19 self-reported illness outcomes for self and family and close friends; perceived changes in family and friend relationships, school engagement, social isolation, and other psychological factors since the COVID-19 pandemic began; and worry over COVID-19-related health outcomes. RESULTS A total of 2559 American Indian students (1201 [46.9%] male; 1284 [50.2%] female; 70 [2.7%] another gender; mean [SD] 14.7 [8.9] years) were included in the analysis. Approximately 14%of the sample reported having had a test result positive for SARS-CoV-2 infection (14.3% [95% CI, 11.4%-17.6%]), a higher rate than for all cases nationally at the time of the survey. Regarding prevalence of COVID-19 among family and close friends, 75.4% (95% CI, 68.8%-80.9%) of participants reported having at least 1 family member or friend who had contracted COVID-19, while 27.9% (95% CI, 18.8%-39.3%) of participants reported that at least 1 family member or close friend had died of COVID-19. Regarding psychosocial impacts, COVID-19 was associated with strained friend relationships (eg, 34.0% [95% CI, 28.4%-40.0%] of students reported worry over losing friends), lower school engagement, and less social connectedness (eg, 62.2% [95% CI, 56.7%-67.4%] of students reported feeling less socially connected to people), although more than 60% of students also reported feeling no change or a decrease in negative emotions. Males were less likely to report perceived negative impacts, especially for negative emotions such as sadness (29.2% [95% CI, 23.3%-35.9%] of males vs 46.1% [95% CI, 43.9%-48.3%] of females reported feeling more sad) and anxiety (21.8% [95% CI, 18.2%-25.8%] of males vs 39.2% [95% CI, 34.1%-44.6%] of females reported feeling more anxious).