Endotoxin can stimulate inflammatory cytokine release from monocytes/macrophages and result in septic shock. Glycyrrhetinic acid (GA), the main bioactive component of licorice, possesses substantial anti-inflammatory activity. Here, we explored effect of 11-deoxy-18α-glycyrrhetinic acid-30-ethyl ester (DGAEE), a newly synthesized derivative of GA, on septic shock. DGAEE and its main metabolite 11-deoxy-18α-glycyrrhetinic acid (DGA) significantly alleviated septic shock as evidenced by improvements of survival rates, lung histopathological changes and wet/dry ratio in lipopolysaccharide (LPS)/D-galactosamine-stimulated mice, and decreased blood pressure in LPS/D-galactosamine-stimulated rats. The two compounds decreased serum levels of NO, TNF-α, IL-6, IL-1β, and increased the level of IL-10 more potently in mice. In LPS-stimulated RAW 264.7 cells, DGA but not DGAEE showed marked regulation of NO, TNF-α, IL-6 and IL-10 levels, suggesting that DGAEE display anti-shock effect by DGA rather than itself. Moreover, the neutralizing antibody against IL-10 markedly prohibited the inhibitory effect of DGA on the production of cytokines from RAW 264.7 cells, and AS101 (an inhibitor of IL-10 biosynthesis) almost completely reversed the anti-shock effect of DGA in mice. In addition, DGA did not affect activation of NF-κB-p65 and p38 MAPK as well as IκBα degradation, but moderately reduced activation of ERK and JNK, and markedly increased phosphorylation of GSK3β in LPS-stimulated RAW 264.7 cells. LY294002 (an inhibitor of GSK3β phosphorylation) and LiCl (an inhibitor of GSK3β activity) diminished and potentiated increase of IL-10 levels by DGA, respectively. In conclusion, DGAEE alleviates septic shock through DGA in an IL-10-dependent manner, and the mechanism is related to inactivation of GSK3β.