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Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β-lapachone (β-LAP), a natural quinone-containing compound, in a mouse model of DOX-induced hepatotoxicity. β-LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. β-LAP ameliorated liver injury and liver function markers evoked by DOX. β-LAP also downregulated the mRNA expression of nuclear factor-kB-corresponding genes including interleukin-6, interleukin-1β, and tumor necrosis factor-α. Moreover, β-LAP increased the nuclear factor erythroid 2-related factor 2 target genes heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD + /NADH ratios and subsequently elevated the protein levels of sirtuin-1 (SIRT-1), farnesoid X receptor (FXR), and phosphorylated AMP-activated protein kinase (p-AMPK). Collectively, these findings suggest a protective role of β-LAP against DOX-induced hepatotoxicity by partly regulating the NAD + /SIRT-1/FXR/p-AMPK axis., (© 2023 Wiley Periodicals LLC.)