Excessive nitric oxide (NO) is often observed in the airways of patients with severe asthma. Here, we show that the NO donor diethylamine NONOate impairs the proliferative capacity of mouse club cells and induces club cell apoptosis, cell cycle arrest, and alterations in lipid metabolism. Our data suggest that NO inhibits club cell proliferation via upregulation of Gdpd2 (glycerophosphodiester phosphodiesterase domain containing 2). During ovalbumin (OVA) challenge, apoptotic club cells are observed, but surviving club cells continue to proliferate. OVA exposure induces Gdpd2 expression; Gdpd2 knockout promotes the proliferation of club cells but inhibits goblet cell differentiation. Elimination of airway NO was found to inhibit goblet cell differentiation from club cells during OVA challenge. Our data reveal that excessive NO might be related to airway epithelial damage in severe asthma and suggest that blockade of the NO‐Gdpd2 pathway may be beneficial for airway epithelial restoration.