Pulmonary fibrosis is a lethal and progressive pulmonary disorder in human beings. Ephedrine is a compound isolated from Ephedra and plays a regulatory role in inflammatory response. This study focused on the anti-pulmonary fibrosis effect of ephedrine and its potential molecular mechanism. After a mouse model of pulmonary fibrosis was established through bleomycin (BLM) induction, the survival percentage, body weight, and pulmonary index were measured. Hematoxylin-eosin staining and Masson's trichrome staining for lung tissues were performed to observe the pathological alterations. The viability of lung epithelial BEAS-2B cells, intracellular production of reactive oxygen species, and the levels of pro-inflammatory cytokines were examined by cell counting kit-8 assays, 2',7'-dichlorofluorescein diacetate (DCF-DA) staining, and enzyme-linked immunosorbent assay, respectively. Immunofluorescence staining was performed to determine E-cadherin and vimentin expression after BLM or ephedrine treatment. The mRNA and protein levels of cytokeratin-8, E-cadherin, α-SMA, and vimentin were subjected to quantitative polymerase chain reaction and immunoblotting. Experimental results revealed that ephedrine treatment rescued the repressive impact of BLM on BEAS-2B cell viability, and ephedrine inhibited BLM-induced overproduction of reactive oxygen species and inflammatory response in BEAS-2B cells. Additionally, ephedrine suppressed epithelial-mesenchymal transition (EMT) process stimulated by BLM treatment, as demonstrated by the reduced α-SMA and vimentin levels together with the increased cytokeratin-8 and E-cadherin levels in BLM + Ephedrine group. In addition, ephedrine inhibited NF-κB and activated Nrf-2 signaling in BLM-treated BEAS-2B cells. Moreover, ephedrine ameliorated pulmonary fibrosis in BLM-induced mice and improved the survival of model mice. In conclusion, ephedrine attenuates BLM-evoked pulmonary fibrosis by repressing EMT process via blocking NF-κB signaling and activating Nrf-2 signaling, suggesting that ephedrine might become a potential anti-pulmonary fibrosis agent in the future.