Background: Knowledge regarding the impact of respiratory pathogen co-infection in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children seeking emergency department care is limited, specifically as it relates to the association between SARS-CoV-2 viral co-infection and disease severity and factors associated with co-infection. Methods: This secondary analysis included data from 2 prospective cohort studies conducted between March 2020 and February 2022 that included children <18 years of age tested for SARS-CoV-2 infection along with additional respiratory viruses in a participating emergency department. Outcomes included the detection rate of other respiratory viruses and the occurrence of severe outcomes (ie, intensive interventions, severe organ impairment and death). Results: We included 2520 participants, of whom 388 (15.4%) were SARS-CoV-2-positive. Detection of additional respiratory viruses occurred in 18.3% (71/388) of SARS-CoV-2-positive children, with rhinovirus/enterovirus being most frequently detected (42/388; 10.8%). In multivariable analyses (adjusted odds ratio and 95% confidence interval), among SARS-CoV-2-positive children, detection of another respiratory virus was not associated with severe outcomes [1.74 (0.80–3.79)], but detection of rhinovirus/enterovirus [vs. isolated SARS-CoV-2 detection 3.56 (1.49–8.51)] and having any preexisting chronic medical condition [2.15 (1.06–4.36)] were associated with severe outcomes. Among SARS-CoV-2-positive children, characteristics independently associated with an increased odds of any other viral co-infection included: age and delta variant infection. Conclusions: Approximately 1 in 5 children infected with SARS-CoV-2 had co-infection with another respiratory virus, and co-infection with rhinovirus/enterovirus was associated with severe outcomes. When public health restrictions were relaxed, co-infections increased.