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Autophagy and apoptosis are powerful regulators of multiple facets of cellular metabolism and homeostasis. Here, we uncover that galanin, a pleiotropic peptide, regulates cardiac autophagy and deactivates apoptotic cell death through the Forkhead box protein O1 (FoxO1) pathway. In hypertrophied heart, galanin promotes autophagy and metabolic shift from fatty acid (FA) to glucose oxidation and preserves mitochondrial integrity. In cardiomyoblasts, galanin triggers autophagosome formation and alleviates hypertrophy, apoptotic cell death, and mitochondrial stress. Mechanistically, galanin dictates cell autophagic and anti-apoptotic phenotypes through FoxO1 pathway. Together, these findings uncover a previously unknown role for galanin in the regulation of cardiac autophagy and provide new insights into the molecular mechanisms supporting cell survival in the hypertrophic reprogramming of the heart., Graphical abstract Image 1, Highlights • Galanin dictates autophagic phenotype in cardiomyoblasts. • Galanin suppresses myocardial apoptosis and mitochondrial oxidative stress in hypertrophic remodeling. • Galanin promotes metabolic shift from fatty acid to glucose oxidation in the hypertrophied hearts. • Galanin regulates cardiac autophagy and apoptosis through FoxO1 pathway.