Objective To investigate the relationship between the levels of growth differentiation factor-15 (GDF-15), vascular endothelial growth factor (VEGF), and CXC chemokine receptor 4 (CXCR4) and in-stent restenosis (ISR) in patients with coronary heart disease after percutaneous coronary intervention (PCI). Methods A total of 118 patients with coronary heart disease admitted to Henan Provincial Rongjun Hospital from March 2021 to June 2022 were selected and all received PCI. They were divided into ISR group (24 cases) and non-ISR group (94 cases) according to whether ISR occurred after PCI. Enzyme-linked immunosorbent assay was used to measure GDF-15 and CXCR4, and double antibody sandwich-enzyme-linked immunosorbent assay was used to measure VEGF. The correlation and predictive value of serum GDF-15, VEGF, CXCR4 and ISR in patients with coronary heart disease after PCI were analyzed. Results The number of coronary lesions and the number of stents implanted in the ISR group were higher than those in the non-ISR group, and the length of coronary lesions was longer than that in the non-ISR group. The preoperative Gensini score, left ventricular ejection fraction (LVEF), D-dimer (D-D), fibrinogen (FIB), GDF-15, and VEGF were higher than those in the non-ISR group, while CXCR4 was lower than that in the non-ISR group, and the differences were statistically significant (P<0.05). Increased levels of FIB, GDF-15, VEGF, and decreased levels of CXCR4 were independent risk factors for the development of ISR after PCI, and the differences were statistically significant (P<0.05). After further adjusting for the influence of FIB, GDF-15, VEGF, and CXCR4 remained associated with the development of ISR after PCI. The AUC of the combined prediction of serum GDF-15, VEGF, and CXCR4 for predicting ISR after PCI was significantly greater than that of each individual predictor, and the differences were statistically significant (P<0.05). Conclusion Serum GDF-15, VEGF and CXCR4 levels are significantly correlated with ISR in patients with coronary heart disease after PCI. All of them have predictive value for ISR, and combined detection can provide more reliable data support for clinical practice.