The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in cystic fibrosis (CF) by improving CFTR-mediated Cl- and HCO3- secretion by airway epithelial cells (AECs), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, have numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression, we exposed primary human AEC to ETI for 48 h and interrogated the transcriptome by RNA-seq and qPCR. ETI increased CFTR Cl- secretion, and defensin gene expression (DEFB1), an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI decreased MMP10 and MMP12 gene expression, suggesting that ETI may reduce proteolytic-induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase (HMOX1). qPCR analysis confirmed DEFB1, HMOX1, MMP10, and MMP12 gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation, and MHC class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug-induced increases in DEFB1 and that ETI may reduce lung damage by reducing MMP10 and MMP12 gene expression. Moreover, pathway analysis also identified several other genes responsible for the ETI-induced reduction in inflammation observed in pwCF.NEW & NOTEWORTHY Gene expression responses by CF AECs exposed to ETI suggest that in addition to improving CFTR channel function, ETI is likely to enhance resistance to bacterial infection by increasing levels of beta-defensin 1 (hBD-1). ETI may also reduce lung damage by suppressing MMP10 and MMP12 and reduce airway inflammation by repressing proinflammatory cytokine secretion by CF AECs.