Drug-coated balloons are the preferred treatment for in-stent restenosis (ISR), avoiding the need for a second metallic layer. While both paclitaxel-coated balloons (PCB) and limus-coated balloons (LCB, typically sirolimus or biolimus) are used, direct comparative evidence is limited, particularly regarding their long-term angiographic efficacy and clinical safety. We conducted a systematic review and study-level meta-analyzis of studies comparing LCB with PCB for coronary ISR. A comprehensive search was performed across PubMed, Embase, Cochrane, Scopus, Web of science for randomized controlled trials. Outcomes were compared using risk ratios (RR) for categorical data and mean differences for continuous data in a random-effects model. Heterogeneity was assessed using the I2 statistic. Six randomized controlled trials involving 1,038 patients were included (552 in the LCB group and 481 in the PCB group). Compared with PCB, LCB were associated with a significantly higher risk of clinically driven target lesion revascularization (RR: 1.48; 95% CI: 1.02 to 2.14; p = 0.04; I2 = 0%) and target lesion failure (RR: 1.19; 95% CI: 0.87 to 1.62; p = 0.27; I2 = 0%). In contrast, both platforms demonstrated no differences in all-cause mortality (RR: 0.98; p = 0.96), myocardial infarction (RR: 0.73; p = 0.46), stent thrombosis (RR: 0.66; p = 0.57), or MACE (RR: 1.09; p = 0.58). Angiographic outcomes were comparable, including late lumen loss (mean differences: -0.00 mm; p = 0.65; I2 = 74.7%) and minimal lumen diameter (mean differences: -0.12 mm; p = 0.07). In patients with ISR, PCB reduced repeat revascularization compared with LCB. These data suggest a modest advantage for PCB in preventing restenosis following drug-coated balloon angioplasty for ISR.