Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase-(GSK-) 3 beta is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3 beta inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3 beta in C57BL/6 mice. GSK-3 beta was activated followingCLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3 beta also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3 beta inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-kappa B) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3 beta inhibition reduced inflammatory cytokine production via modulation of NF-kappa B and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3 beta blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-kappa B and CREB activity and suppression of hepatic apoptosis.