〔Abstract〕 Objective To investigate the expression and clinical significance of serum soluble growth stimulating gene 2 protein expression (sST2), C-reactive protein (CRP) and sphingosine-1-phosphate (S1P) in patients with critical coronary artery disease. Methods A total of 90 patients diagnosed with critical coronary artery disease in the First Affiliated Hospital of Henan University from July 2021 to July 2023 were selected as the observation group, and another 90 patients with definite ischemic lesions on electrocardiogram but no stenosis by coronary angiography were selected as the control group. The differences in serum sST2, CRP, and S1P levels between the two groups were compared, and correlation analysis was used to explore the correlation between serum sST2, CRP, S1P levels in the observation group and their Gensini scores, and the observation group was divided into subgroups based on whether functional myocardial ischemia occurred and their risk factors were analyzed. Results The serum levels of sST2, CRP, and S1P in the observation group were significantly higher than those in the control group, with statistical significances (P < 0.05). The serum levels of sST2, CRP and S1P in the observation group were positively correlated with Gensini score (r = 0.3811, r = 0.3788, r = 0.6162, P < 0.001). In the observation group, the serum levels of sST2, CRP, and S1P in the ischemic subgroup were significantly higher than those in the non-ischemic subgroup, with statistical significance (P < 0.05). Multivariate logistic regression analysis showed that serum sST2, CRP, and S1P levels were independent risk factors for myocardial ischemia in patients with coronary artery disease (P < 0.05). Conclusion The abnormal elevation of serum sST2, CRP, and S1P levels in patients with critical coronary artery disease is related to the degree of coronary artery stenosis, and the abnormal elevation of serum sST2, CRP, and S1P levels is an independent risk factor for functional myocardial ischemia in patients with critical coronary artery disease.