AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, has been shown to exert a protective effect against cardiac hypertrophy and heart failure. Our previous reports have demonstrated that AMPK can inhibit cardiac hypertrophy and block the development of heart failure by promoting autophagy. However, other investigators have demonstrated that overactive and dysregulated autophagy may also contribute to the onset and exacerbation of heart failure. Thus, a major goal of the present investigation is to explore how AMPK regulates autophagy in heart failure. First, heart failure was induced in mice by 4 weeks of pressure overload; AMPK activation was subsequently induced by injecting 5-aminoimidazole-4-carboxamide 1-beta-n-ribonucleotide (AICAR) after the establishment of chronic heart failure. We showed that AMPK activation significantly attenuated the progression of heart failure and improved cardiac function, which was accompanied by decreased autophagy levels in the failing hearts. Additionally, we demonstrated that the treatment with AICAR inhibited phosphorylation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) downstream effectors 4E-binding protein 1 (4EBP1), and ribosomal protein S6 kinase (p7OS6K). A major action of AICAR was significantly to activate AKT (Ser(473)), the downstream substrate of mTOR complex 2 (mTORC2). In conclusion, the data suggest that AMPK improved cardiac function during the development of chronic heart failure by attenuating autophagy, potentially via mTORC2 activation and the downstream effects.