Single-cell analysis of blood samples from 66 infants revealed fundamentally different immune strategies against RSV and SARS-CoV-2 infections. While both viruses triggered comparable interferon responses, RSV specifically increased CD4+ terminal effector memory T cells and memory regulatory T cells in circulation. Severe RSV cases showed compromised natural killer cell function, with reduced IFNG expression and diminished chromatin accessibility at key transcription factor binding sites. SARS-CoV-2 infections instead activated heightened inflammatory pathways, including nuclear factor κB signaling and elevated serum TNF concentrations. These findings illuminate why RSV causes more severe lower respiratory tract disease in infants despite SARS-CoV-2's broader pandemic impact. The distinct immune signatures suggest RSV may exploit regulatory mechanisms that dampen protective responses, while COVID-19 triggers inflammatory cascades that paradoxically remain manageable in young children. This mechanistic understanding could inform targeted therapeutic approaches, particularly for severe RSV where natural killer cell dysfunction appears central to pathogenesis. The work also validates systems immunology approaches for dissecting age-specific disease susceptibility patterns that epidemiological data alone cannot explain.