This study aims to explore the roles of miR-145/TGFBR2 axis in sepsis-induced acute lung injury. Here, RNA-sequencing assay showed that miR-145 was significantly decreased in exosomes from sepsis patient blood samples. And miR-145 was decreased but TGFBR2 was increased in LPS-treated mice lung tissues or BEAS-2B cells in a time-dependent manner. Mechanistically, TGFBR2 was identified as a direct target of miR-145 and the downstream effector Smad3 was also suppressed in BEAS-2B cells with miR-145 overexpression. Pre-injection or post-injection of miR-145 agomir following LPS treatment attenuated LPS-induced inflammation, characterized as the downregulation of IL-2 and TNF-α secretion and ameliorate sepsis, and prolonged the overall survival of septic mice with lung injury. Additionally, TGFBR2 overexpression partially abrogated miR-145-mediated inhibition on LPS-induced inflammation and sepsis-induced acute lung injury. Importantly, TGF-β (Transforming growth factor-β) and miR-145 level displayed a negative correlation in sepsis patients. Thus, these results suggest that miR-145 could ameliorate sepsis-induced lung injury via inhibiting TGFBR2 signaling.