BACKGROUND: FGF21 is a stress-inducible hormone that operates in the autocrine or paracrine manner. Recent reports have revealed that FGF21 is highly expressed in cardiac hypertrophy to protect against heart injury and dysfunction. FGF21 is used to treat cardiac hypertrophy in mouse models. However, preclinical and clinical trials are restricted. AIM OF REVIEW: This review mainly elucidates the diverse functions of FGF21 and explores the relationship between these functions and cardiac hypertrophy. It also discusses challenges and future perspectives in treating cardiac hypertrophy with FGF21. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review first illustrates the functions of FGF21, including energy metabolism, inflammation, oxidative stress, apoptosis, and autophagy. We also summarize vital functions and the underlying mechanisms through which FGF21 regulates the initiation and development of cardiac hypertrophy, connecting energy metabolism, inflammation, oxidative stress, apoptosis, and autophagy. Finally, we propose that FGF21 may be a potential therapeutic strategy for cardiac hypertrophy.