Mitigating the risks of antibiotic resistance requires a horizon scan linking the quality with the quantity of data reported on drivers of antibiotic resistance in humans, arising from the human, animal, and environmental reservoirs. We did a systematic review using a One Health approach to survey the key drivers of antibiotic resistance in humans. Two sets of reviewers selected 565 studies from a total of 2819 titles and abstracts identified in Embase, MEDLINE, and Scopus (2005–18), and the European Centre for Disease Prevention and Control, the US Centers for Disease Control and Prevention, and WHO (One Health data). Study quality was assessed in accordance with Cochrane recommendations. Previous antibiotic exposure, underlying disease, and invasive procedures were the risk factors with most supporting evidence identified from the 88 risk factors retrieved. The odds ratios of antibiotic resistance were primarily reported to be between 2 and 4 for these risk factors when compared with their respective controls or baseline risk groups. Food-related transmission from the animal reservoir and water-related transmission from the environmental reservoir were frequently quantified. Uniformly quantifying relationships between risk factors will help researchers to better understand the process by which antibiotic resistance arises in human infections.