Abstract Background Paraquat (PQ) is an herbicide widely used in the world. PQ can cause pulmonary toxicity and even acute lung injury. Treatment for PQ poisoning in a timely manner is still a challenge for clinicians. Mesenchymal stem cell (MSC) transplantation has hold potentials for the treatment of several lung diseases including PQ poisoning. The aim of this study is to examine the mechanisms mediated by MSC transplantation to protect PQ-induced lung injury. Methods Here we performed the whole genome sequencing and compared the genes and pathways in the lung that were altered by PQ or PQ together with MSC treatment. Results The comparison in transcriptome identified a combined mitigation in NF-kappaB signaling and IL-17 signaling in MSC transplanted samples. Conclusion This study not only reiterates the important role of NF-kappaB signaling and IL-17 signaling in the pathogenesis of PQ-induced toxicity, but also provides insight into a molecular basis of MSC administration for the treatment of PQ-induced toxicity.