Purpose: To investigate the safety and efficacy of drug-coated balloons (DCB) for the treatment of femoropopliteal or infrapopliteal lesions in patients with chronic limb-threatening ischemia (CLTI). Materials and Methods: A systematic literature search was conducted in PubMed, Scopus, and Cochrane Central up to January 2020 to identify randomized trials and observational studies presenting data on the effectiveness and safety of DCBs in the treatment of femoropopliteal or infrapopliteal lesions. A meta-analysis utilizing random effects modeling was conducted to investigate primary patency and all-cause mortality at 12 months; the results are reported as the odds ratios (ORs) and 95% confidence intervals (CIs). Secondary outcomes were procedural success, bailout stenting, target lesion revascularization (TLR), reocclusion, major amputation, wound healing, and major adverse limb events. Results: Twenty-six studies, 12 retrospective and 14 prospective, comprising 2108 CLTI patients treated with DCBs for femoropopliteal (n=1315) or infrapopliteal (n=793) lesions were analyzed. The average lesion lengths were 121±44 and 135±53 mm, respectively. The overall 12-month all-cause mortality and major amputation rates were 9% (95% CI 6% to 13%) and 5% (95% CI 2% to 8%), respectively. Primary patency rates were 82% (95% CI 76% to 87%) and 64% (95% CI 58% to 70%), respectively. A sensitivity analysis of the infrapopliteal lesions demonstrated no difference between DCB and balloon angioplasty in terms of primary patency, TLR, major amputation, or mortality over 12 months. However, patients with infrapopliteal lesions undergoing DCB angioplasty did have a significantly lower risk for reocclusion (10% vs 25%; OR 0.38, 95% CI 0.21 to 0.70, p=0.002). Conclusion: DCB angioplasty of femoropopliteal and infrapopliteal lesions in patients with CLTI results in acceptable 12-month patency rates, although comparative data have not shown a patency benefit for infrapopliteal lesions. The 12-month mortality rate of DCB vs balloon angioplasty was not significantly different, but studies with longer-term outcomes are necessary to determine any association between DCB use and mortality in patients with CLTI.