Record-breaking and devastating rainfall events have occurred in the past decade. Rain and floods are considered the main risk factors for leptospirosis and several outbreaks have been reported following extreme weather events. In such situations, one possible intervention to prevent leptospirosis cases in high-risk groups is the use of chemoprophylaxis. However, not enough evidence of its effect is available. The objectives of this study were to review the literature on the current practices of chemoprophylaxis for leptospirosis and to explore, using a mathematical model, how various chemoprophylaxis scenarios may affect the progression of a leptospirosis outbreak. Twenty-six peer-reviewed publications were selected (10 quantitative studies, two systematic reviews and 14 articles of other types). Oral doxycycline was the most used antibiotic for chemoprophylaxis of leptospirosis. Post-exposure prophylaxis was assessed in four studies following a natural disaster. Although evidence of the effectiveness of post-exposure prophylaxis is inconsistent, the direction of association supported a protective effect for morbidity and mortality. The theoretical model showed how the assumed benefit of chemoprophylaxis was influenced by the time and rate of administration. Future models should consider the heterogeneity of affected communities, improved estimates of the effect of chemoprophylaxis on leptospirosis infection and disease, as well as potential detrimental impacts. Additional research is critical to provide clear evidence-based recommendations for leptospirosis control during an outbreak. The results of this study suggest that chemoprophylaxis may provide some protection in reducing the number of leptospirosis cases after a high-risk exposure; however, the effective benefit may depend on a variety of factors such as the timing and coverage of prophylaxis. The information summarized can be used to support decision-making during a high-risk event.