Inhalation of fine atmospheric particulate matter (PM) with a diameter smaller than 2.5 μm (PM_2.5) has been linked to an increased risk of respiratory damage, hospital admissions, and respiratory-related fatalities. While the exact mechanism connecting PM_2.5 exposure to negative health outcomes remains unclear, oxidative stress caused by PM_2.5 is believed to play a critical role in its toxicity. CGK012 [(7S)-(+)-cyclopentyl carbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester] is a newly developed small-molecule inhibitor of the Wnt/β-catenin pathway. This study aimed to explore the protective effects of CGK012 against PM_2.5-induced oxidative damage and to uncover the mechanisms involved. Human pulmonary artery endothelial cells (HPAECs) were exposed to PM_2.5 followed by CGK012 treatment. PM_2.5 exposure reduced HPAEC viability in a dose- and time-dependent manner, likely due to increased lactate dehydrogenase release and elevated intracellular reactive oxygen species (ROS). The oxidative damage was linked to changes in superoxide dismutase and catalase activities, as well as downregulation of SGK1, a key cell survival factor. CGK012 treatment, however, improved cell survival, decreased oxidative stress, and restored SGK1 expression. Additionally, CGK012 increased mTOR phosphorylation and significantly inhibited PM_2.5-induced expression of toll-like receptor 4 (TLR4), MyD88, and autophagy markers LC3 II and Beclin 1. These results suggest that CGK012 offers protection against PM_2.5-induced lung damage by targeting oxidative stress and mTOR-dependent autophagy pathways, positioning it as a potential treatment for PM_2.5-related respiratory injury.