Pathological cardiac hypertrophy contributes to the development of heart failure (HF). NOL1/NOP2/Sun domain family member 2 (NSUN2) is implicated in pathophysiological processes of many diseases. However, the function and operation of NSUN2 in cardiac hypertrophy and HF remain unclear. Here, we observed a significant increase in the levels of NSUN2 expression in both human hearts with HF and in mouse hearts with hypertrophy induced by transverse aortic constriction (TAC) and angiotensin II (Ang II) treatment. Cardiomyocyte-specific knockout of NSUN2 attenuated the reduced cardiac ejection fraction (EF) and fractional shortening (FS) and the increased heart weight to tibial length (HW/TL) upon either TAC or Ang II infusion. Conversely, cardiac-specific overexpression of NSUN2 resulted in cardiac remodeling as indicated by a prominent increase in hypertrophic growth and cardiac fibrosis and a robust decline in cardiac EF and FS. Mechanistically, NSUN2 induces 5-methylcytosine (m5C) modification of La-related protein 1 (LARP1) to enhance its messenger RNA (mRNA) stability, which is mediated by Y-box binding protein 1 (YBX1). Increased LARP1 further interacts with GATA binding protein 4 (GATA4) mRNA and prevents its degradation. LARP1 silencing partially attenuates TAC and NSUN2 induced cardiac hypertrophy and HF. Collectively, this study provides a new insight into the central role of NSUN2 in cardiac hypertrophy, indicating that NSUN2 may serve as a novel therapeutic target for HF.