Pulmonary fibrosis is highly lethal with limited treatments. Butaselen (BS) is an inhibitor of thioredoxin reductase (TrxR)/thioredoxin (Trx) with anti-tumor activity. However, its impact on pulmonary fibrosis and the involved mechanisms remain unclear. Here, we demonstrate that BS is a potential drug for the treatment of pulmonary fibrosis. Specifically, BS can inhibit pulmonary fibrosis both in vitro and in vivo, with comparable efficacy and enhanced safety when compared with pirfenidone. BS and dexamethasone display a synergistic effect in inhibiting pulmonary fibrosis both in vitro and in vivo. Mechanistic studies reveal that BS can inhibit the TrxR activity during pulmonary fibrosis. RNA-sequencing analysis identifies that genes of ECM-related signaling pathways are notably affected by BS. BS can not only inhibit the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and reduce pulmonary fibrosis-related inflammation, but also reduce NF-κB-activated transcriptional expression of transforming growth factor-β1 (TGF-β1), which leads to the inactivation of Smad2/Smad3 and decrease of collagen formation and fibrosis. Moreover, the knockdown of Trx1 with siRNA can also inhibit NF-κB/TGF-β1/Smads signaling. In conclusion, the TrxR/Trx inhibitor butaselen can suppress pulmonary fibrosis by inhibiting NF-κB/TGF-β1/Smads signaling.