Background: Doxorubicin (DOX) induced hepatorenal injury is a major health concern. Amentoflavone (AMF) is a biflavonoid with conspicuous pharmacological activities. Objective: To clarify the possible protective AMF effect on DOX associated hepatorenal injury & the possible underlying mechanisms. Material and methods: 30 rats were equally divided to three groups: control group. DOX group and DOX+AMF treated. After that blood samples were withdrawn for assessment of serum urea, creatinine, ALT, AST, MDA, TNF-α, caspase-3, SOD and IL10. Liver and kidney were preserved for AKT, PI3K and GSK-3β genes expression level detection. Finally, Histopathological assessment of hepatic and renal section was done. Results: DOX group revealed a significant increase in urea, creatinine, ALT, AST, MDA, TNF-α, and caspase-3, along with a concurrent decrease in SOD and IL10 when compared to control rats. Serum levels of urea, creatinine, ALT, AST, MDA, TNF-α, caspase3 were significantly reduced, and SOD and IL10 were significantly increased in the DOX+AMF group compared to DOX group, while there was a significant reduction in the expression of the AKT and PI3K genes and a concurrent increase in the expression of the GSK-3β gene with DOX treatment. AMF significantly mitigated the expression of the AKT and PI3K genes with reduction of GSK-3β gene after 8 weeks. Conclusion: AMF protects against doxorubicin induced hepatorenal injury by antioxidant, anti-inflammatory, anti-apoptotic mechanisms in addition to modulation in PI3K/AKT/GSK-3β signaling pathway.