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Acute liver failure (ALF) is a complex syndrome characterized by overactivation of innate immunity, and the recruitment and differentiation of immune cells at inflammatory sites. The present study aimed to explore the role of microRNA (miRNA/miR)-21 and its potential mechanisms underlying inflammatory responses in ALF. Baseline serum miR-21 was analyzed in patients with ALF and healthy controls. In addition, miR-21 antagomir was injected via the tail vein into C57BL/6 mice, and lipopolysaccharide/D-galactosamine (LPS/GalN) was injected into mice after 48 h. The expression levels of miR-21, Krüppel-like-factor-6 (KLF6), autophagy-related proteins and interleukin (IL)-23, and hepatic pathology were then assessed in the liver tissue. Furthermore, THP-1-derived macrophages were transfected with a miRNA negative control, miR-21 inhibitor, miR-21 mimics or KLF6 overexpression plasmid, followed by treatment with or without rapamycin, and the expression levels of miR-21, KLF6, autophagy-related proteins and IL-23 were evaluated. The results revealed that baseline serum miR-21 levels were significantly upregulated in patients with ALF. In addition, LPS/GalN-induced ALF was attenuated in the antagomir-21 mouse group. KLF6 was identified as a target of miR-21-5p with one putative seed match site identified by TargetScan. A subsequent luciferase activity assay demonstrated a direct interaction between miR-21-5p and the 3′-UTR of KLF6 mRNA. Further experiments suggested that miR-21 promoted the expression of IL-23 via inhibiting KLF6, which regulated autophagy. In conclusion, in the present study, baseline serum miR-21 levels were highly upregulated in patients with ALF, antagomir-21 attenuated LPS/GalN-induced ALF in a mouse model, and miR-21 could promote the expression of IL-23 via inhibiting KLF6. [ABSTRACT FROM AUTHOR]