Heart failure (HF) is a serious and chronic condition. Methyltransferase like 14 (METTL14) is an important component of the m6A methyltransferase complex. This study seeks to explore the mechanism by which METTL14 regulates cardiomyocyte pyroptosis in mice with HF, providing a novel target for HF treatment. Both mouse and cell models were treated with doxorubicin (DOX) to induce HF, followed by measurement of heart function parameters and myocardial damage marker. Next, in cell models, the expression of METTL14, miR-221-3p, pri-miR-221, LncRNA FTX, SESN2, and pyroptosis-related factors was detected. The m6A levels of pri-miR-221, the bindings of miR-221-3p to LncRNA FTX and FUS to LncRNA FTX or SESN2, and the interaction between miR-221-3p and LncRNA FTX were detected. We found that METTL14 was overexpressed in mouse and cell models. METTL14-mediated m6A modification upregulated miR-221-3p expression and inhibited LncRNA FTX expression, reducing the binding of LncRNA FTX to FUS, ultimately inhibiting SESN2 expression. Knockout of METTL14 improved heart function, as evidenced by increased EF and FS, decreased LVIDd and LVIDs, and reduced CK, CK-MB, and LDH, and reduced cardiomyocyte pyroptosis (the levels of cleaved Caspase-1, GSDMD-N, NLRP3, IL-18, and IL-1β were decreased). miR-221-3p overexpression or SESN2 downregulation partially reversed the protective effects of METTL14 downregulation on cardiomyocyte pyroptosis and HF. In conclusion, METTL14-mediated m6A modification exacerbates cardiomyocyte pyroptosis and HF through the miR-221-3p/LncRNA FTX/SESN2 axis, highlighting a potential therapeutic target for HF.