Aim To investigate the risk factors of in-stent restenosis (ISR) within 2 years after the implantation of drug-eluting stent (DES) in patients with coronary heart disease and type 2 diabetes, and construct a Nomogram prediction model. Methods Clinical data of patients with coronary heart disease and type 2 diabetes who received DES at the Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen from January 2010 to February 2020 were retrospectively analyzed. The PASS estimation model generates cohort sample size, which was divided into ISR group (DES-ISR) and non-ISR (non-DES-ISR) group based on the results of coronary angiography. The single factor and conditional multivariate Logistic regression analysis were performed on the parameters with statistical significance between the two groups, and the Nomogram prediction model was constructed and its reliability was verified in the validation cohort. Results A total of 1 741 cases were included in model generated cohort, 233 cases (13.4%) were diagnosed with ISR within 2 years after implantation of DES. Conditional multivariate Logistic regression analysis showed that the predictor of DES-ISR was estimated glomerular filtration rate (eGFR)＜60 mL/(min·1.73 m²) (OR＝2.7,5%CI:1.41～5.47, P＝0.003), dyslipidemia (OR＝1.0,5%CI:1.30～2.78, P＝0.001), fasting blood glucose (FPG) ≥6.5 mmol/L (OR＝5.0,5%CI:3.05～9.92, P＜0.001), multivessel coronary artery disease (OR＝7.6,5%CI:3.27～16.11, P＜0.001), diffuse coronary artery disease (OR＝1.0,5%CI:1.13～2.88, P＝0.014), primary PCI operation time ≥60 min (OR＝2.2,5%CI:1.13～6.05, P＝0.024) and emergency PCI (OR＝2.0,5%CI:1.48～3.28, P＜0.001). The model validation cohort contained 102 cases, the risk of DES-ISR increased with the increase of the Nomogram scores. The area under the receiver operating characteristic (ROC) curve of the Nomogram model was 0.791 (95%CI:0.753～0.829, P＝0.019). Conclusions The anatomical characteristics of coronary artery and PCI procedures are important predictors of DES-ISR. Nomogram can effectively identify high-risk groups of DES-ISR and provide effective decision-making information for follow-up and intervention of high-risk groups.