objective: To investigate the effect of honokiol (HKL) for reducing doxorubicin (DOX)-induced cardiotoxicity in H9c2 cells and the underlying mechanisms. methods: H9c2 cells were divided into control group, DOX group, HKL + DOX group, and HKL+compound C+DOX group. After 24 h of corresponding treatment, the cells were examined for morphological changes and cell viability using CCK-8 assay. The mRNA expressions of the inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by RT-PCR, and the protein levels of cleaved caspase-3, cytochrome c, NOD-like receptor pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), p-AMPK and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) were detected with Western blotting; the expressions of NLRP3 and p-AMPK also detected with immunofluorescence staining. results: DOX treatment caused swelling and significantly lowered the viability of H9c2 cells ( < 0.05), resulting also in increased mRNA expressions of TNF-α, IL-6 and IL-1β ( < 0.05) and protein expressions of cleaved caspase-3, cytochrome c, NLRP3, caspase-1 and ASC ( < 0.05) but reduced protein levels of p-AMPK and Nrf2 ( < 0.05); fluorescence staining showed significantly increased NLRP3 expression and decreased expression of p-AMPK in DOX-treated cells ( < 0.05). All these changes in COX-treated cells were significantly alleviated by HKL treatment ( < 0.05). The application of compound C obviously mitigated the protective effects of HKL against DOX-induced cardiotoxicity in H9c2 cells. conclusions: HKL can alleviate DOX-induced cardiotoxicity by inhibiting pyroptosis in H9c2 cells, and this effect is mediated by activation of AMPK to regulate Nrf2 signaling.