Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (β1i/β2i/β5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.