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Sepsis is the most common cause of acute kidney injury (AKI), which is associated with increased morbidity and mortality. The molecular mechanisms underlying sepsis pathogenesis and its regulation are incompletely understood. Here we demonstrated that human AlkB homologue, ALKBH8, plays a critical role in sepsis. We found that ALKBH8 expression was down-regulated in patients with acute sepsis. Low expression of ALKBH8 was also confirmed in LPS-induced sepsis model. Functionally, we revealed that knockdown of ALKBH8 in THP-1 cells suppressed cell proliferation and promoted cell apoptosis. In contrast, overexpression of ALKBH8 enhanced cell viability and protected against oxidative damage in THP-1 cells. In addition, we demonstrated that knockdown of ALKBH8 enhanced oxidative stress and decreased selenocysteine-protein expression. Mechanistically, we found that ALKBH8 ameliorated inflammation response via blocking NFκB/NLRP3 signaling in THP-1 cells. Inhibition of ROS production by using N -acetylcysteine (NAC) antagonized the effect of ALKBH8 knockdown on inflammation response and NFκB/NLRP3 signaling activation in THP-1 cells. Taken together, these results strongly suggest that ALKBH8 is an important oxidative stress and inflammation regulator in sepsis, which might have potential clinical application in the treatment of sepsis. Ethics: All patients provided written informed consent and the study protocols were approved by the Ethics Committee of Xiʹan Jiaotong University. The investigation conforms to the principles outlined in the Declaration of Helsinki and written informed consent was obtained from all participants. Funding: The work was supported by Key Research and Development Projects of Shaanxi Province of China (2020SF-121) Shaanxi Administration of Traditional Chinese Medicine Research Program (JCMS037). Competing interests: None