Leptospirosis is an acute febrile disease that mainly affects developing countries with tropical climates. The complexity and magnitude of this disease is attributed to socioeconomic, climatic, and environmental conditions. In this study, in a 10-year period from 2008 to 2017, the relationship between human leptospirosis cases and climatic factors in Cartagena de Indias, Colombia were evaluated. Monthly leptospirosis cases, climatic variables, and macroclimatic phenomena (El Niño and La Niña) were obtained from public datasets. Local climatic factors included temperature (maximum, average, and minimum), relative humidity, precipitation, and the number of precipitation days. Time series graphs were drawn and correlations between cases of leptospirosis and climatic variables considering lags from 0 to 10 months were examined. A total of 360 cases of leptospirosis were reported in Cartagena during the study period, of which 192 (53.3%) were systematically notified between October and December. Several correlations were detected between the number of cases, local climatic variables, and macroclimatic phenomena. Mainly, the increase of cases correlated with increased precipitation and humidity during the La Niña periods. Herein, seasonal patterns and correlations suggest that the climate in Cartagena could favor the incidence of leptospirosis. Our findings suggest that prevention and control of human leptospirosis in Cartagena should be promoted and strengthened, especially in the last quarter of the year.