Background: Sepsis is a life-threatening condition and often associated with multiple organ failure. Nuclear-enriched abundant transcript 1 (NEAT1), a member of long non-coding RNAs (lncRNAs), was reported to be involved in the regulation of sepsis progression. However, its precise regulatory mechanism needs to be further explored. Methods: CCK-8 assay was utilized to check cell viability. The qRT-PCR was employed to detect the expression levels of NEAT1, miR-370-3p and iIrak2. Flow cytometry assay and ELISA were used to check cell apoptosis and the concentrations of inflammatory cytokines, respectively. The starBase was used to predict binding sites between miR-370-3p and NEAT1 or Irak2 and the dual-luciferase reporter assay was performed to verify the interaction. The protein level of Irak2 in samples was measured by western blot. Results: The high concentration of lipopolysaccharide (LPS) led to the high death ratio of RAW 264.7 and HL-1 cells. Besides, NEAT1 and Irak2 were upregulated in sepsis tissues and LPS-induced RAW 264.7 and HL-1 cells, opposite to the expression of miR-370-3p. In addition, knockdown of NEAT1 promoted viability, suppressed apoptosis and reduced the expression of inflammatory cytokines in LPS-induced RAW 264.7 and HL-1 cells. Moreover, we found that miR-370-3p interacted with NEAT1 and targeted the 3'UTR of Irak2. Further research indicated that downregulation of miR-370-3p or upregulation of IraK2 rescued NEAT1 silencing-mediated inhibitory effect on sepsis progression. Conclusion: Knockdown of NEAT1 hampered sepsis progression by downregulating Irak2 via interacting with miR-370-3p in LPS-induced RAW 264.7 and HL-1 cells.