Background: Drug-coated balloons (DCBs) have become increasingly vital to percutaneous coronary intervention, offering many advantages. However, a significant challenge is that many patients are intolerant to the myocardial ischemia caused by DCB dilation. Remote ischemic preconditioning (RIPC) is known to enhance heart’s tolerance to ischemia and hypoxia. This study investigated whether preoperative RIPC could extend the tolerated DCB inflation time and improve the long-term prognosis of patients with coronary artery disease (CAD). Methods: A total of 653 patients with CAD were recruited and randomized into a RIPC group (n = 323) and a control (n = 330) group. The RIPC group underwent RIPC on the left upper limb twice daily, starting three days before the DCB implantation. The patients were followed up for one year after the operation, and 197 patients returned for coronary angiography (CAG) examination where the quantitative flow ratio (QFR) of the target vessels was measured. The primary endpoint of the study was the incidence of target lesion failure (TLF), which included target lesion revascularization (TLR), target vessel myocardial infarction, and cardiac death. The secondary endpoint was the rate of QFR loss in the target vessels. Results: The findings revealed a significantly lower incidence of TLR in the RIPC group compared to the control group. Additionally, at the one-year follow-up, the rate of QFR loss in target vessels was lower in the RIPC group than in the control group. Conclusions: The preoperative application of RIPC effectively extended the duration patients could tolerate DCB inflation. Furthermore, this approach positively impacted the long-term prognosis of CAD patients undergoing DCB treatment. Clinical Trial Registration Information: NCT04766749.