Cardiac remodelling, a pathological process induced by various cardiovascular diseases, remains a significant challenge in clinical practice. Here, we investigate the potential of Danuglipron (PF-06882961, PF), a novel oral glucagon-like peptide-1 (GLP-1) receptor agonist, in alleviating pressure overload (PO)-induced cardiac hypertrophy and fibrosis. Using both in vivo and in vitro models, we demonstrate that PF treatment (1 mg/kg/day, orally for 8 weeks) significantly attenuates aortic banding-induced cardiac dysfunction and pathological remodelling in mice. Mechanistically, we show that PF mitigates apoptotic responses and enhances autophagy by promoting AMPK phosphorylation and increasing HSP70 expression. Notably, the cardioprotective effects of PF are abolished in AMPKα2 knockout mice, with no observable increase in HSP70 levels. Our findings reveal a previously unrecognised role of PF in cardiac protection, mediated through the AMPKα-HSP70 signalling pathway, and suggest its potential as a therapeutic strategy for PO-induced cardiac remodelling.