Ozone (O3) is a prevalent air pollutant that causes lung inflammation following exposure. Previous studies demonstrate that O3 oxidizes lipids, such as cholesterol, in the airway to produce oxidized cholesterol products (oxysterols), such as secosterol-A (secoA), which form covalent linkages preferentially with lysine residues and consequently modify protein function. The breadth of proteins modified by this oxysterol as well as the biological consequences in the lung are unknown. Using an alkynyl-tagged form of secosterol-A and shotgun proteomics, we identified NLR Family Pyrin Domain Containing 2 (NLRP2) to be adducted at lysine (K1019) in the terminal leucine-rich-repeat, a known regulatory region for NLR proteins. We characterized NLRP2 expression in airway epithelial cells and used CRISPR-Cas9 knockout and shRNA knockdown of NLRP2 for analysis of inflammasome complex activity and pro-inflammatory mediator production following O3 exposure. We observed an increase in caspase-1 activity in response to O3, which was not altered by knocked down NLRP2 expression. O3-induced pro-inflammatory gene expression for CXCL1, CXCL2, and IL8 was further enhanced in NLRP2 knockout cells. Together, our findings uncover NLRP2 as a highly abundant, key component of pro-inflammatory signaling pathways in airway epithelial cells and formation of oxysterol-NLRP2 adduct as a novel mediator of O3-induced inflammation.