Dexamethasone is a glucocorticoid that is used for the treatment of interstitial pneumonia and pulmonary fibrosis as it possesses anti-inflammatory and anti-fibrosis properties. In the current study, A549 cells were exposed to paraquat, dexamethasone, or both of them, to investigate the potential effect of dexamethasone against paraquat-triggered poisoning in A549 cells. The inflammatory response was evaluated by measuring tumor necrosis factor-α, interleukin-1β, and interleukin-6 while the degree of fibrosis was assessed by detecting collagen I and fibronectin using enzyme-linked immunosorbent assay. Western blotting was used to assess the protein expression of apoptotic proteins as well as transforming growth factor-β1, Smad 3 and phospho-Smad 3. DNA ladder assay was performed to estimate DNA damage in different groups of the alveolar epithelial cells. Dexamethasone protected against paraquat-induced inflammatory response as shown by the significantly reduced levels of the pro-inflammatory cytokines and it also alleviated paraquat-provoked fibrosis as it substantially diminished collagen I and fibronectin levels. Moreover, dexamethasone remarkably decreased the relative expression levels of transforming growth factor-β1 and phospho-Smad3 that were upregulated upon PQ treatment. Dexamethasone also protected against paraquat-induced genotoxicity and apoptosis. In conclusion, dexamethasone may protect against paraquat-induced inflammation, fibrosis, genotoxicity, and apoptosis via modulating TGF-β1/Smad 3 signaling pathway.