The prevalence of heart failure (HF), including reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), has increased significantly worldwide. However, the prognosis and treatment of HF are still not good. Recent studies have demonstrated that high-density lipoprotein (HDL) plays an important role in cardiac repair during HF. The exact role and mechanism of HDL in the regulation of HF remain unexplained. Here, we discuss recent findings regarding HDL in the progression of HF, such as the regulation of excitation-contraction coupling, energy homeostasis, inflammation, neurohormone activation, and microvascular dysfunction. The effects of HDL on the regulation of cardiac-related cells, such as endothelial cells (ECs), cardiomyocytes (CMs), and on cardiac resident immune cell dysfunction in HF are also explained. An in-depth understanding of HDL function in the heart may provide new strategies for the prevention and treatment of HF.