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Introduction The airway epithelial barrier continues to develop during the first year of life, representing a critical time window of susceptibility to the effects of respiratory viruses that may contribute to the development of childhood asthma. This study specifically aimed to assess the impact of respiratory syncytial virus (RSV) infection on the longitudinal development of the airway epithelium, airway metabolism, DNA methylation and subsequent childhood asthma.Methods and analysis The Wheezing, Asthma and Viral effects on the Epithelial Structure and function (WAVES) birth cohort study is a prospective, observational birth cohort that is enrolling mother–child dyads beginning in pregnancy and following children through age 5 years. It is designed as a quasi-natural randomisation of RSV infection in infancy, capturing the first RSV infection event during infancy and longitudinal nasal sampling from birth through age 5 years for multi-omic assays and assessment of clinical outcomes. The WAVES study protocol will enrol 250 pregnant women and their offspring (200 at high-risk for asthma and 50 at general-risk for asthma). The primary outcomes are pathways through which RSV infection intersects with airway epithelial development leading to asthma by age 5 years. We will employ a longitudinal systems biology approach to investigate the development of the airway epithelium following infant RSV infection in those who do and do not develop asthma. This approach will integrate single-cell and bulk RNA-sequencing gene expression, metabolomic and epigenetic data at the resolution of epithelial cell subsets.Ethics and dissemination This study has been approved by the Vanderbilt University Medical Center IRB (#222277), and study results will be communicated in peer-reviewed publications and to the study participants and lay community. By analysing these longitudinal multi-omic datasets, we aim to uncover key mechanisms driving airway epithelial development and identify how these processes are altered by early-life RSV infection and contribute to the development of early-life respiratory morbidity and asthma.