Background Drug-eluting balloon (DEB) has become an alternative option to drug-eluting stent (DES) for the treatment of in-stent restenosis (ISR). However, the effect of drug-eluting balloon with regular bare-mental stent (BMS) in de novo coronary artery disease (CAD) is unclear. This meta-analysis aimed to evaluate the efficacy of DEB with regular BMS compared to BMS or DES in de novo CAD. Methods Randomized controlled trials (RCTs) assessing the efficacy of DEB+BMS in comparison with BMS or DES were obtained by searching the PubMed, EMBASE, and Cochrane Library databases through January 2016. Primary endpoints were major adverse cardiac events (MACEs) and late lumen loss (LLL). Secondary endpoints included death, myocardial infarction (MI), target lesion revascularization (TLR), stent thrombosis (ST), binary restenosis, and minimum lumen diameter (MLD). Dichotomous and continuous data were presented as odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs), respectively, and analyzed using a random-effects model. Results A total of 14 RCTs involving 2281 patients were included in this meta-analysis. DEB+ BMS showed significantly less MACEs (OR: 0.67, 95% CI 0.45 to 0.99, P = 0.04) and reduced LLL (MD: -0.30 mm, 95% CI: -0.48 mm to -0.11 mm, P = 0.001) compared with BMS. Meanwhile, treatment with DEB+ BMS had disadvantages over DES in terms of MACEs (OR: 1.94, 95% CI 1.24 to 3.05, P = 0.004), LLL (MD: 0.20 mm, 95% CI: 0.07 mm to 0.33 mm, P = 0.003), TLR (OR: 2.53, 95% CI 1.36 to 4.72, P = 0.003), and MLD (MD: -0.25 mm, 95% CI: -0.42 mm to -0.09 mm, P = 0.003). Conclusions This limited evidence demonstrated that treatment with DEB+BMS appears to be effective in de novo CAD. In addition, DEB+BMS clearly showed superiority to BMS, but is inferior to DES in the treatment of patients with de novo CAD. Hence, DES (especially new generation DES) should be recommended for patients with de novo CAD.