Objective To investigate the relationship between the expression of serum angiopoietin?like protein 8 （ANGPTL8） and Kruppel?like factor 2 （KLF2） and the degree of coronary artery disease and the occurrence of major adverse cardiac events （MACE） in patients with acute myocardial infarction （AMI）. Methods A total of 106 patients with AMI who were hospitalized in our hospital from January 2021 to June 2023 were selected as the research objects. According to the degree of coronary artery disease， the patients were grouped into mild group （52 cases） and severe group （54 cases）. According to the occurrence of MACE， the patients were grouped into MACE group （18 cases） and non?MACE group （88 cases）. General patient data were collected. Serum ANGPTL8 and KLF2 levels were detected by enzyme?linked immunosorbent assay （ELISA）. Spearman correlation analysis was applied to analyze the correlation between serum ANGPTL8 and KLF2 levels and Gensini score in AMI patients. Multivariate logistic regression was applied to analyze the influencing factors of coronary artery disease degree in patients with AMI. Receiver operating characteristic （ROC） curves were drawn to analyze the value of serum ANGPTL8 and KLF2 levels in predicting the occurrence of MACE in AMI patients. Results The proportions of patients with history of hypertension and hyperlipidemia， systolic blood pressure， diastolic blood pressure， levels of triacylglycerol （TG）， N?terminal pro?B?type natriuretic peptide （NT?proBNP）， cardiac troponin I （cTnI）， Gensini score， and level of serum ANGPTL8 in the severe group were higher than those in the mild group （P < 0.05）. The level of high?density lipoprotein cholesterol （HDL?C） and serum KLF2 in the severe group were lower than those in the mild group （P < 0.05）. The number of lesions in the mild group and the severe group was statistically obvious （P < 0.05）. Serum ANGPTL8 level in AMI patients was positively correlated with Gensini score （r = 0.638， P < 0.05）， and serum KLF2 level was negatively correlated with Gensini score （r = -0.612， P < 0.05）. History of hypertension， hyperlipidemia， cTnI and ANGPTL8 were risk factors for the progression of severe coronary artery disease in patients with AMI （P < 0.05）， while HDL?C and KLF2 were protective factors （P < 0.05）. The serum level of ANGPTL8 in AMI patients in the MACE group was higher than that in the non?MACE group （P < 0.05）， and the serum KLF2 level in the MACE group was lower than that in the non?MACE group （P < 0.05）. The area under the curve of serum ANGPTL8 and KLF2 levels and their combination in predicting the occurrence of MACE in AMI patients was 0.740 （95%CI： 0.646 ~ 0.820）， 0.799 （95%CI： 0.710 ~ 0.870）， and 0.806 （95%CI： 0.717 ~ 0.876）， respectively. Conclusion The expressions of serum ANGPTL8 and KLF2 are closely related to the degree of coronary artery disease in patients with AMI， and have certain predictive value for the occurrence of MACE.