Acute kidney injury (AKI)results inretention of waste products anddysregulation of extracellular volume and electrolytes, thus leading to a variety of complications. Recent advances in long noncoding RNAs suggested their close relationship with disease progression. In the current study, we investigated the role and mechanism of maternally expressed gene 3 (MEG3) on AKI pathogenesis. Real-time polymerase chain reaction found that the expression of MEG3 was significantly increased in both kidney tissues and TKPTS cells induced by lipopolysaccharide (LPS). Western blot assay showed that the expression of apoptosis regulator Bcl-2 was increased in MEG3-inhibited TKPTS cells. Flow cytometry assay confirmed that LPS-induced apoptosis was significantly attenuated after transfection of si-MEG3. The RNAhybrid informatics algorithm predicted that there was a strong binding capacity between miR-21 and MEG3. Luciferase reporter assay confirmed that MEG3 could function as a competing endogenous RNA of miR-21. The antiapoptotic effect of si-MEG3 could be neutralized by a miR-21 inhibitor, demonstrated by the decreased expression of Bcl-2 and flow cytometry results. Further investigation showed that programmed cell death protein 4 (PDCD4), a validated target of miR-21, was highly expressed in both injured kidney tissues and LPS-stimulated TKPTS cells. Meanwhile, the protein expression of PDCD4 was significantly reduced by inhibition of MEG3, but retrieved by coinhibition of MEG3 and miR-21. In conclusion, our results demonstrated that inhibition of MEG3 could attenuate LPS-induced apoptosis in TKPTS cells by regulating the miR-21/PDCD4 pathway, suggesting that the MEG3/miR-21/PDCD4 axis could be developed as a potential therapeutic target of AKI.