School-based interventions during epidemics are often controversial, as experienced during the COVID-19 pandemic, where reducing transmission had to be weighed against the adverse effects on young children. However, it remains unclear how the broader epidemiologic context influences the effectiveness of these interventions and when they should be implemented. Through integrated modeling of epidemiological and genetic data from a longitudinal school-based surveillance study of SARS-CoV-2 in 2021-2022 (N children = 336, N adults = 51) and scenario simulations, we show how transmission dynamics in schools changed markedly due to strong increases in community-acquired infections in successive periods of viral variants, ultimately undermining the potential impact of school-based interventions in reducing infection rates in the school-aged population. With pandemic preparedness in mind, this study advocates for a dynamic perspective on the role and importance of schools in infectious disease control, one that adapts to the evolving epidemiological landscape shaped by pathogen characteristics and evolution, shifting public health policies, and changes in human behavior.