Objective To investigate the content of copeptin (CPP) and kallistatin (KS) in serum of patients with coronary atherosclerosis (CAS) and their relationship with the degree of coronary artery stenosis. Methods The clinical data of 196 patients with CAS treated in our hospital from October 2019 to October 2020 were selected, and the clinical data of 190 healthy persons of the same age were collected at the same time. Taking the patients with CAS as the observation group and the healthy persons as the control group. The differences of CPP, KS and clinical data were compared. The independent risk factors of CAS was analyzed by binary Logistic regression. The predicting value of CPP and KS in the diagnosis of severe CAS were evaluated by the receiver working characteristic curve (ROC). Results CPP of the observation group was significantly higher than that of the control group, while KS was significantly lower than that of the control group (all P＜0.05). CPP increases with the degree of increasing CAS stenosis, while KS decreases with the degree of increasing CAS stenosis (all P＜0.05). Binary Logistic regression analysis showed that CPP, KS and high density lipoprotein were independent risk factors for the occurrence of CAS (all P＜0.05). The ROC curve showed that the AUC value (0.830) of CPP combined with KS was significantly higher than that of a single CPP or KS (0.758 or 0.741), and its sensitivity and specificity were 86.54 and 87.97, respectively (all P＜0.05). Conclusion In serum, CPP increased in CAS and KS decreased in CAS, both of which are closely related to the degree of CAS stenosis. Moreover, CPP combined with KS has a good diagnostic efficacy for severe CAS stenosis, which is of great significance for guiding the early clinical prevention and treatment.