Background: Outcomes of SARS CoV-2 infection in infants, children and young adults are reported less frequently than in older populations. The evolution of SARS-CoV-2 cases in LA County youths followed at a large health network in southern California over two years was evaluated. Methods: A prospective cohort study of patients aged 0–24 years diagnosed with COVID-19 was conducted. Demographics, age distribution, disease severity, circulating variants of concern (VOCs), and immunization rates were compared between first and second pandemic years. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) of factors associated with severe/critical COVID-19. Results: In total, 61,208 patients 0–24 years of age were tested for SARS-CoV-2 by polymerase chain reaction (PCR); 5263 positive patients (8.6%) with available data were identified between March 2020 and March 2022. In Year 1, 5.8% (1622/28,088) of youths tested positive, compared to 11% (3641/33,120) in Year 2 (p< 0.001). Most youths had mild/asymptomatic illness over two years. SARS-CoV-2 positivity was >12% across all age groups in the second half of Year 2, when Omicron prevailed. Pulmonary disease was associated with higher risk of severe COVID-19 in both years (OR: 2.4, 95% CI: 1.4–4.3,p= 0.002, Year 1; OR: 11.3, 95% CI: 4.3–29.6, Year 2,p< 0.001). Receipt of at least one COVID-19 vaccine dose was protective against severe COVID-19 (OR: 0.3, 95% CI: 0.11–0.80,p< 0.05). Conclusions: Despite different VOCs and higher rates of test positivity in Year 2 compared to Year 1, most youths with COVID-19 had asymptomatic/mild disease. Underlying pulmonary conditions increased the risk of severe COVID-19, while vaccination was highly protective against severe disease in youths.