Diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher mortality due to the more frequent development of subsequent pathological myocardial remodelling and concomitant functional deterioration. This study investigates the molecular pathways underlying accelerated cardiac remodelling in a well-established mouse model of diabetes exposed to MI.Myocardial infarction in DM mice was established by ligating the left anterior descending coronary artery. Cardiac function was assessed by echocardiography. Myocardial hypertrophy and cardiac fibrosis were determined histologically 6 weeks post-MI or sham operation. Autophagy, the NLRP3 inflammasome, and caspase-1 were evaluated by western blotting or immunofluorescence. Echocardiographic imaging revealed significantly increased left ventricular dilation in parallel with increased mortality after MI in DM mice (53.33%) compared with control mice (26.67%, P < 0.05). Immunoblotting, electron microscopy, and immunofluorescence staining for LC3 and p62 indicated impaired autophagy in DM + MI mice compared with control mice (P < 0.05). Furthermore, defective autophagy was associated with increased NLRP3 inflammasome and caspase-1 hyperactivation in DM + MI mouse cardiomyocytes (P < 0.05). Consistent with NLRP3 inflammasome and caspase-I hyperactivation, cardiomyocyte death and IL-1β and IL-18 secretion were increased in DM + MI mice (P < 0.05). Importantly, the autophagy inducer and the NLRP3 inhibitor attenuated the cardiac remodelling of DM mice after MI.In summary, our results indicate that DM aggravates cardiac remodelling after MI through defective autophagy and associated exaggerated NLRP3 inflammasome activation, proinflammatory cytokine secretion, suggesting that restoring autophagy and inhibiting NLRP3 inflammasome activation may serve as novel targets for the prevention and treatment of post-infarct remodelling in DM.© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.