Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection hospitalizations in infants and poses a significantly higher risk of respiratory failure than SARS-CoV-2. The mechanisms underlying these differences remain unclear. We analyzed blood samples from infants (median age 2.3 months) with SARS-CoV-2 (n = 30), RSV (n = 19), and healthy controls (n = 17) using single-cell transcriptomics and epigenomics, and cytokine profiling. Both viruses triggered comparable interferon responses across PBMC subsets but differed in NK cell and inflammatory responses. Severe RSV cases showed reduced NK cell frequencies, lower