Integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network. When the body encounters adverse stimuli, ISR is activated to assist cells, tissues, and the body in adapting to the changing environment and maintaining health by reprogramming genes. ISR is implicated in the onset and progression of various diseases, including cardiovascular disease, diabetes, obesity, cancer, and neurological disorders. A key factor in ISR is the eukaryotic initiation factor 2α (eIF2α) kinase. Four eIF2α kinases have been identified, namely general control non-derepressible-2 (GCN2), protein kinase double-stranded RNA-dependent (PKR), PKR-like ER kinase (PERK), and heme-regulated inhibitor (HRI). GCN2, PKR, PERK, and HRI kinases share a common kinase catalytic domain but have distinct regulatory domains that are activated by endoplasmic reticulum stress (ERS), viral infection, heme deficiency, and amino acid deficiency, respectively. Various stress conditions promote the phosphorylation of eIF2α at serine 51 by its 4 kinases. This inhibits the eIF2B-mediated GTP acquisition of eIF2α and reduces the translation rate. At the same time, ISR upregulates ATF4 expression. ATF4 and CCAAT-enhancer binding protein (CHOP) can promote downstream growth arrest and DNA damage-inducible protein 34 (GADD34) to mediate eIF2α dephosphorylation. At the same time, it can promote the downstream expression of Sestrin 2 (SESN2) protein, increase autophagy induced by mTORC1 and AMPK, and thereby reduce the risk of cardiovascular disease. Numerous animal and cellular studies have demonstrated that exercise, drugs, and molecular compounds can prevent and improve pathological myocardial hypertrophy, diabetic cardiomyopathy, ischemic cardiomyopathy, cardiotoxicity, and atherosclerosis by modulating ISR. The relevant mechanism involves gene knockout or inhibitors that directly inhibit the expression of eIF2α kinase. Aerobic exercise, editing of specific molecules, or drugs can indirectly inhibit the expression of eIF2α kinase, ultimately leading to the inhibition of the downstream expression of eIF2α/ATF4. In light of the significant pathological role of ISR in cardiovascular disease, current research on ISR primarily aims to develop medications that can regulate the upstream and downstream signaling activities of ISR. This involves targeting ISR to regulate intracellular protein homeostasis, ultimately aiming to delay or reverse the progression of cardiovascular disease. At present, drugs targeting ISR in cardiovascular disease research mainly include ISRIB, 4-PBA, and Salubrinal. ISRIB reverses eIF2α phosphorylation by suppressing the inhibitory effect of eIF2α on protein synthesis and blocking eIF2α/ATF4 signaling. 4-PBA can inhibit endoplasmic reticulum stress. Salubrinal inhibits eIF2α dephosphorylation by inhibiting the binding of GADD34-PP1 and CReP-PP1 complexes to eIF2α. In conclusion, the integrated stress response mediated by the four eIF2α kinases is essential for the body to adapt to various stress stimuli affecting the heart and blood vessels under normal or pathological conditions. Integrated stress response inhibitors should be promptly administered to clinical cardiovascular patients to assess their effectiveness in the onset and development of various cardiovascular diseases, as well as to evaluate potential side effects. Future studies are needed to explore the role and mechanism of eIF2α kinase-mediated integrative stress response in various diseases. It is also essential to investigate whether the integrative stress response yields different effects in various organs and can potentially exert cross-organ efficacy through inter-organ interaction.