Spermidine is an endogenous biological polyamine that plays various longevity-extending roles and exerts antioxidative, antiaging, and cell growth-promoting effects. We previously reported that spermidine levels were significantly reduced in idiopathic pulmonary fibrosis (IPF) of the lung. The present study assessed the potential beneficial effects of spermidine on lung fibrosis and investigated the possible mechanism. Lung fibrosis was established in mice using bleomycin (BLM), and exogenous spermidine was administered daily by intraperitoneal injection (50 mg/kg in phosphate-buffered saline). BLM-induced alveolar epithelial cells showed significant increases in apoptosis and endoplasmic reticulum stress (ERS)-related mediators, and spermidine attenuated BLM-induced apoptosis and activation of the ERS-related pathway. Senescence-associated β-gal staining and decreased expression of p16 and p21 showed that spermidine ameliorated BLM-induced premature cellular senescence. In addition, spermidine enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts and BLM-induced mouse lungs, in which inflammation and collagen deposition were significantly decreased. This beneficial effect was related to the antiapoptotic downregulation of the ERS pathway, antisenescence effects, and autophagy activation. Our findings suggest that spermidine could be a therapeutic agent for IPF treatment.