Asthma and other airway obstructive disorders are characterized by heightened inflammation and excessive airway epithelial cell reactive oxygen species (ROS), which give rise to a highly oxidative environment. After decades of use, β2-adrenergic receptor (β2AR) agonists remain at the forefront of treatment options for asthma, however, chronic use of β2-agonists leads to tachyphylaxis to the bronchorelaxant effects, a phenomenon that remains mechanistically unexplained. We have previously demonstrated that β2AR agonism increases ROS generation in airway epithelial cells, which upholds proper receptor function via feedback oxidation of β2AR cysteine thiolates to Cys-S-sulfenic acids (Cys-SOH). Our previous results also demonstrate that prevention of normal redox cycling of this post-translational oxi-modification back to the thiol prevents proper receptor function. Given that Cys-S-sulfenic acids can be irreversibly overoxidized to Cys-S-sulfinic (Cys-SO₂H) or S-sulfonic (Cys-SO₃H) acids, which are incapable of further participation in redox reactions, we hypothesized that β2-agonist tachyphylaxis may be explained by hyperoxidation of β2AR to S-sulfinic acids. Here, using airway epithelial cell lines and primary small airway epithelial cells from healthy and asthma-diseased donors, we show that β2AR agonism generates H₂O₂ in a receptor and NAPDH oxidase-dependent manner. We also demonstrate that acute and chronic receptor agonism can facilitate β2AR S-sulfination, and that millimolar H₂O₂ concentrations are deleterious to β2AR-mediated cAMP formation, an effect that can be rescued to a degree in the presence of the cysteine-donating antioxidant N-acetyl-_L-cysteine. Our results reveal that the oxidative state of β2AR may contribute to receptor functionality and may, at least in part, explain β2-agonist tachyphylaxis.