Pulmonary fibrosis (PF) is a chronic, progressive, irreversible, fibrotic interstitial lung disease with high mortality. Ginsenoside Re (G-Re) is one of the active components of ginseng, which has been proven to possess multiple pharmacological effects, including anti-inflammatory and antioxidant. Thus, G-Re is considered a potential therapeutic agent for treating PF. The present study explored the protective mechanisms of G-Re against bleomycin (BLM)-induced PF in mice and its potential as a therapeutic strategy for PF. A mouse model of BLM-induced PF was utilized to assess the effect of G-Re treatment, with N-acetylcysteine (NAC) set as a positive control agent. Various parameters such as lung function, histopathological changes, oxidative stress markers, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and its related protein expressions, including Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1), and ferroptosis signature protein glutathione peroxidase 4 (GPX4) were evaluated. Continuous administration of G-Re for 14 days significantly reduced lung injury, enhanced antioxidant capacity, activated the Nrf2/Keap1 signaling pathway, and inhibited ferroptosis as evidenced by GPX4. Additionally, G-Re treatment reduced collagen deposition, improved pulmonary function, and alleviated oxidative stress in the lung tissue of PF mice. These findings demonstrate that G-Re exerts its therapeutic effects against PF by modulating the Nrf2/Keap1/GPX4 axis and targeting oxidative stress and ferroptosis pathways, highlighting the potential of G-Re as a pharmacological intervention for PF and providing insights into the molecular mechanisms underlying its protective effects.