Objective To compare the effects of intra-tracheal drip and intratracheal nebulized spray of bleomycin (5 mg/ kg) on the rat model of pulmonary fibrosis, and to compare the effects of intraperitoneal 3% pentobarbital sodium anesthesia and isoflurane respiratory anesthesia (isoflurane concentration of 0. 5% when mixed with oxygen for inhalation) on the rat model of pulmonary fibrosis, and to explore a more optimal modeling method. Methods Fifty male SPF-grade SD rats were randomly divided into blank control group, intraperitoneal anesthetic intratracheal drip group, intraperitoneal anesthetic intratracheal nebulizer spray group, respiratory anesthetic intratracheal drip group and respiratory anesthetic intratracheal nebulizer spray group, 10 rats in each group. The survival status and body weight of rats in each group were observed at 1, 3, 7, 14 and 21 d after drug administration; rats were executed 3 weeks after drug administration, and lungs were weighed to calculate lung coefficients; HE staining was performed to observe inflammatory changes in lung tissues; Masson staining was performed to observe collagen proliferation in lung tissues; Western Blot was performed to detect transforming growth factor-β1 (TGF-β1) protein expression in lung tissues; alkali hydrolysis was performed to detect hydroxyproline (HYP) in lung tissues. Results Compared with the blank control group, the rats in the four model groups had poor mental status, decreased body weight, and increased lung index; lung tissue damage was evident, increased inflammation levels, and significant collagen proliferation; increased TGF-β1 protein expression levels in lung tissues (P<0. 001); and increased hydroxyproline levels in lung tissues of rats in the intratracheal nebulizer sprayed with bleomycin only group were found ( P< 0. 05). The modeling approach of intratracheal drip injection was found to have a heterogeneous distribution of fibrotic lesions in the lungs of its model rats, with varying degrees of fibrosis. The mean time to awakening and mortality rates were lower in rats under isoflurane respiratory anesthesia (0. 5% isoflurane concentration when mixed with oxygen for inhalation) than in the intraperitoneal 3% pentobarbital sodium anesthesia modality when both anesthesia levels were medium. Conclusions Intratracheal nebulized spray of bleomycin under isoflurane respiratory anesthesia is the preferred modeling method for establishing a rat model of pulmonary fibrosis.