To identify risk factors for persistent impairments after pediatric hospitalization for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C) during the SARS-CoV-2 pandemic. Across 25 U.S. Network hospitals, we conducted a prospective cohort study of patients <21-years-old hospitalized for acute COVID-19 or MIS-C (May 2020 to March 2022) surveyed 2- to 4-months post-admission. Multivariable regression was used to calculate adjusted risk ratios (aRR) and 95% confidence intervals (CI). Of 232 children with acute COVID-19, 71 (30.6%) had persistent symptoms and 50 (21.6%) had activity impairments at follow-up; for MIS-C (  = 241), 56 (23.2%) had persistent symptoms and 58 (24.1%) had activity impairments. In adjusted analyses of patients with acute COVID-19, receipt of mechanical ventilation was associated with persistent symptoms aRR 1.83 (95% CI: 1.07, 3.13) whereas obesity aRR 2.18 (95% CI: 1.05, 4.51) and greater organ system involvement aRR 1.35 (95% CI: 1.13, 1.61) were associated with activity impairment. For patients with MIS-C, having a pre-existing respiratory condition was associated with persistent symptoms aRR 3.04 (95% CI: 1.70, 5.41) whereas obesity aRR 1.86 (95% CI: 1.09, 3.15) and greater organ system involvement aRR 1.26 (1.00, 1.58) were associated with activity impairments. Among patients hospitalized, nearly one in three hospitalized with acute COVID-19 and one in four hospitalized with MIS-C had persistent impairments for ≥2 months post-hospitalization. Persistent impairments were associated with more severe illness and underlying health conditions, identifying populations to target for follow-up.