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Objective To study the protective effect and related mechanisms of short-chain fatty acid sodium acetate on hypoxia/reoxygenation (H/R)-induced injury of human renal tubular epithelial cell line HK2. Methods The H/R model was established, and HK2 cells were incubated with sodium acetate (SA) for 2 h. The survival rate of HK2 cells was detected by CCK8 assay; Enzyme activity kit was used for detection of inflammatory factors, cellular reactive oxygen species and ATP production; Flow cytometry was used to measure mitochondrial membrane potential (MMP) and mitochondrial oxidative stress products (mitoSOX) levels; Electron microscope was used to observe mitochondrial ultrastructural damage; Western blot was used to detected the expression of inflammatory signaling pathway IκB-α/NF-κB and mitochondrial energy disorder signaling pathway AMPK/PGC-1α. Results Compared with the control group, the survival rate of HK2 cells in the H/R group was significantly decreased(P＜0.05); the expression of intracellular ROS, mitoSOX and inflammatory factors was significantly increased(P＜0.05); the ultrastructure of mitochondria was severely damaged, and the content of ATP and MMP was significantly decreased(P＜0.05); it was further found that the protein expression of p-IκB-α and NF-κB-p-P65 was significantly increased while the protein expression of p-AMPK and PGC-1α was significantly decreased(P＜0.05). Compared with H/R group, SA significantly enhanced the survival rate of HK2 cells (P＜0.05); SA inhibited the release of intracellular ROS, mitoSOX and inflammatory factors; SA inhibited mitochondrial ultrastructural damage, decreased ATP and MMP (P＜0.05); SA promoted the expression of p-AMPK and PGC-1α and inhibited the expression of p-IκB-α and NF-κB-p-P65 (P＜0.05). Conclusions Sodium acetate plays a protective role with potential mechanisms of anti-inflammation, anti-oxidative stress, protection of mitochondrial structure and function of HK2 cells induced by H/R through inhibiting IκB-α/ NF-κB and activating AMPK/PGC-1α signal pathway.