In septic acute kidney injury, one of the main purposes of long noncoding RNA (lncRNA) ZFAS1 is still unclear. This study is intended to analyze the effects of lncRNA ZFAS1 on the septic AKI in the HK-2 cell line. Materials and Methods . In order to construct an in vitro model of septic AKI, HK-2 cells have been treated with lipopolysaccharides. CCK-8 assay has been utilized to check the viability of HK-2 cells. The contents of inflammatory cytokines (that includes IL-1 β , TNF- α , and IL-6) have been marked with enzyme-linked immune sorbent assay (ELISA). Cell apoptosis was assessed by TUNEL staining. To detect the expression of lncRNA ZFAS1 and microRNA-372-3p, quantitative reverse-transcription PCR has been used. And to confirm the connection among genes, luciferase reporter assay has been applied. Results . Overexpression of ZFAS1 alleviated LPS‐induced HK-2 cell injury. ZFAS1 positively regulated expression of α receptor activated by peroxisome proliferation (PPAR α ) through competitive linkage with miR-372-3p. In addition, over expression of miR-372-3p counteracted the protective effect of upward regulation of ZFAS1 on LPS-induced HK-2 cell damage, which could be reversed by over expression of PPAR α . Conclusion . It is concluded that, in LPS-induced HK-2 cell injury, ZFAS1 has a protective role via modulating the miR-372-3p/PPAR α axis, suggesting the potential of ZFAS1 as a protective target for septic AKI.