Abstract The development of the airway epithelium in asthma is unclear. We characterized nasal airway epithelial cell (NAEC) developmental phenotypes from children aged 2 to 3 years in an a priori designed nested birth cohort from four mutually exclusive groups of wheezers/nonwheezers and respiratory syncytial virus (RSV)–infected/uninfected in the first year of life. NAECs were differentiated, followed by single-cell RNA sequencing analysis and in vitro RSV infection. Gene expression of NAECs from children with a wheeze phenotype indicated abnormal differentiation and basal cell activation of developmental pathways, plasticity in precursor differentiation, delayed onset of maturation, increased diversity of RSV receptors, and blunted antiviral immune responses to in vitro RSV infection. The most marked changes in differentiation were observed in NAECs from children with both wheeze and RSV in the first year of life. Together, this suggests that airway epithelium in children with wheeze is developmentally reprogrammed and characterized by increased barrier permeability, decreased antiviral response, and altered RSV receptor expression.