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• UPLC-Q-TOF-MS and R software were used to identify YSH absorbable chemicals and predict its treatment mechanism. • The efficacy of YSH in alleviating chronic liver injury was studied for the first time. • YSH absorbable chemicals treat chronic liver injury by regulating AKT phosphorylation. Chronic liver injury (CLI) is a complex condition that requires effective therapeutic interventions. The Yi-Shan-Hong (YSH) formula is an empirically derived remedy that has shown effectiveness and safety in the management of chronic liver damage. However, the bioactive components and multifaceted mechanisms of YSH remain inadequately understood. To examine the bioactive compounds and functional processes that contribute to the therapeutic benefits of YSH against CLI. Serum pharmacochemistry and network pharmacology were employed to identify active compounds and possible targets of YSH in CLI. In addition, YSH was also given in three doses to d -(+)-galactosamine hydrochloride (D -GalN) -induced CLI rats to test its therapeutic efficacy. The analysis of serum samples successfully detected 25 compounds from YSH. Searches on the databases resulted in 277 genes as being correlated with chemicals in YSH, and 397 genes associated with CLI. In vivo experiments revealed that YSH displayed a notable therapeutic impact on liver injury caused by d -GalN. This was evidenced by enhanced liver function and histopathological improvements, reduced oxidative stress response, proinflammatory factors, and fibrosis levels. Importantly, no discernible adverse effects were observed. Furthermore, the administration of YSH treatment reversed the activation of AKT phosphorylation caused by d -GalN, aligning with the findings of the network pharmacology study. These findings provide preclinical evidence of YSH's therapeutic value in CLI and highlight its hepatoprotective action via the PI3K/AKT signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]