Aim To investigate the correlation between serum endothelial cell specific molecule-1 (ESM-1), hypoxia-inducible factor-1α (HIF-1α) levels and in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) in patients with unstable angina pectoris (UAP). Methods 202 patients with UAP who underwent PCI in our hospital from March 2018 to April 2019 were selected as the research objects. According to whether ISR occurred within 1 year of postoperative follow-up, the patients were divided into two groups:56 cases in ISR group and 146 cases in non-ISR group. Enzyme-linked immunosorbent assay was used to detect serum ESM-1 and HIF-1α levels in patients 24 h after PCI. The predictive value of serum ESM-1 and HIF-1α levels on ISR and the factors affecting ISR were analyzed. Results The proportion of smoking history, blood glucose, LDLC level, serum ESM-1 and HIF-1α levels in the ISR group were higher than those in the non-ISR group, and the difference was statistically significant (P＜0.05). Serum ESM-1 levels were positively correlated with HIF-1α levels in ISR patients after UAP PCI (r＝0.545, P＜0.05). The area under the ROC curve (AUC) of serum ESM-1 and HIF-1α predicting ISR in UAP patients after PCI were 0.913 and 0.851, respectively, the specificities were 87.0% and 74.0%, and the sensitivities were 82.1% and 85.7%, respectively; the AUC of the joint prediction of the two was 0.936, the specificity was 91.8%, and the sensitivity was 78.6%. ESM-1 (≥2.42 μg/L) and smoking were the independent risk factors affecting ISR in UAP patients after PCI (P＜0.05). Conclusion Increased serum ESM-1 and HIF-1α levels are closely related to the occurrence of ISR after PCI in UAP patients.