Background and Purpose Pulmonary fibrosis (PF) is an irreversible lung disease with little efficient treatments. Epithelial-mesenchymal transition (EMT) in alveolar type II (AT II) cells is an initial process for PF in response to multiple insults. We previously identified paraquat (PQ), inducing acute lung injury and PF, as an agonist for STIM1, promoting STIM1-TRPC1 association for intracellular calcium burden and thus EMT. Here, we investigated the strategy targeting STIM1-TRPC1 association and excessive calcium influx in treating PF. Experimental approach Co-immunoprecipitation was for STIM1-TRPC1 association analysis. Western blotting and Real-time quantitative reverse transcription PCR (QPCR) were for EMT analysis. Calcium imaging, flow cytometry, and luciferase report assay were for analyzing calcium signaling. ELISA, histomorphology, and PQ-poisoned mice or cynomolgus model were for evaluating the efficacy of lysine in treating PF. Retrospective analysis was for analyzing the correlation between the severity of PQ poisoning and blood calcium levels. Key Results Lysine treatment significantly reduces PQ-raised STIM1-TRPC1 association, excessive calcium influx, and thus EMT in AT II cells. As a result, lysine treatment strikingly decreases the mortality of PQ-poisoned mice, with a fully recovery of PQ-induced PF. Immune cells activation, largely occurred accompanied with epithelial damages and PF, are almost normalized with lysine treatment in PQ-poisoned cynomolgus model. A negative correlation between the blood calcium levels and the prognosis were observed in PQ-poisoned patients. Conclusions and Implications These results demonstrate lysine as a potential antidote for PQ-induced PF and provide evidence for maintaining calcium homeostasis as a potential strategy for treating PF.