Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place.The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) againstthe hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel(DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups(DTXL, CTXL, EPIL or DTXH, CTXH, EPIH), and low or high dose chemotherapeutics+APS groups (DTXL+APS,CTXL+APS, EPIL+APS or DTXH+APS, CTXH+APS, EPIH+APS). Controls were treated with equivalent normalsaline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or highdoses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group wereseparately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS(100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanineaminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructuremorphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points.With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and ASTwere significantly increased. Sections of liver tissue showed massive hepatotoxicity in CTXH group comparedto the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis inhepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatinaggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that theprotein levels of caspase-3 increased in CTXH group. The low dose groups exhibited trivial hepatotoxicity. Moreinterestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities(low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes andthe protein levels of caspase-3 (CTXH+APS group). In conclusion, DTX, CTX and EPI induce liver damage ina dose dependent manner, whereas APS exerted protective effects.