While the use of drug-eluting stents (DES) has become the first-line strategy for treating coronary artery disease, there are still drawbacks with their use. As our understanding of coronary artery anatomy and physiology evolves, growing evidence supports the use of drug-coated balloons (DCB) not only in the treatment of in-stent restenosis but also in de novo lesions. The aim of this systematic review and meta-analysis is to determine if there is a difference in outcomes when DCBs are used versus when stents are used. PubMed, Cochrane and Web of Science databases were systematically searched. The primary outcome of the meta-analysis was acute vessel closure and the secondary outcomes were stent complications including major adverse cardiovascular events (MACE) and all-cause mortality. Eleven studies with a total of 2349 patients were included. No significant difference was found in terms of acute vessel closure between DCBs and all stents (2.6% vs. 1.0%, OR: 2.13 (0.74–6.44), I2: 4%, p = 0.16). Furthermore, there was no difference in MACE (6.8% vs. 10.1%, OR: 0.53 (0.27–1.04), I2: 48%, p = 0.06), all-cause mortality and target lesion revascularisation. This meta-analysis suggests that the use of DCBs is a safe alternative to stents when treating coronary artery disease.