Glycyrrhizin (GL) from licorice alleviates intracerebral hemorrhage (ICH) injuries by interacting with high-mobility group box (HMGB) 1, an inflammatory factor. We found that GL is bioconverted by endophyte coexisting with licorice and succeeded in isolating two derivatives. The aim of this study was to identify the compound with more potent HMGB1 inhibitory activity inspired by these GL derivatives. We took advantage of a ketone introduced by an endophyte at the C-3 position and attempted methyl esterification at the C-30 position because it was suggested that the water or lipid solubility of the molecule plays an important role. Among three derivatives synthesized, the product that is both ketonized and esterified showed more potent HMGB1 inhibitory activity than GL in macrophages and significantly improved adverse events occurred in ICH in vivo. These results suggest that modification of the hydrophilicity of GL, particularly at the C-3 and C-30 positions, enhances the HMGB1 inhibitory activity.