Objective: To explore the molecular mechanism of Res in regulation of pulmonary fibrosis (PF). Methods: Rats were injected with bleomycin (BLM) to establish a PF model and treated with resveratrol (Res) and/or miR-21 agomir. After 14 days, lung tissues were collected for Hematoxylin-eosin and Masson's staining, and real-time quantitative polymerase chain reaction and Western blot were performed to detect fibrosis-related protein expression and the activation of the TGF-beta 1/Smad pathway. In vitro, MRC-5 cells were pretreated with TGF-beta 1, Res, and/or miR-21 agomir. After 48 h, total soluble collagen was detected with a Sircol Soluble Collagen Assay. Subsequently, a miR-21 mimic was transfected into MRC-5 cells, and a luciferase reporter assay was employed to verify whether miR-21 targeted Smad7. Results: Res reversed the increased levels of miR-21 induced by BLM and alleviated serious PF symptoms, but agomiR-21 treatment effectively impaired the above manifestations. In vivo, miR-21 inhibited the decreases of TGF-beta 1 and p-Smad2/3 that were induced by Res. In vitro, miR-21 significantly disrupted the positive effect of Res on TGF-beta-induced collagen deposition, as well as the levels of Fn, alpha-SMA, p-Smad2, and Smad7. In addition, Smad7 was found to be a direct target of miR-21-5p. TGF-beta stimulation led to an enormous increase in p-c-Jun, c-Jun, and c-Fos, which were significantly reduced by Res. Finally, miR-21 sharply reduced the increased phosphorylation levels of ERK, JNK and p38 that were induced by Res. Conclusion: Res inhibits BLM-induced PF by regulating miR-21 through MAPK/AP-1 pathways.