Human leptospirosis outbreaks still persistently occur in part of China, indicating that leptospirosis remains an important zoonotic disease in the country. Spatiotemporal pattern of the high-risk leptospirosis cluster and the key characteristics of high-risk areas for leptospirosis across the country are still poorly understood. Using spatial analytical approaches, we analyzed 8,158 human leptospirosis cases notified during 2005–2016 across China to explore the geographical distribution of leptospirosis hotspots and to characterize demographical, ecological and socioeconomic conditions of high-risk counties for leptospirosis in China. During the period studied, leptospirosis incidence was geographically clustered with the highest rate observed in the south of the Province of Yunnan. The degree of spatial clustering decreased over time suggesting changes in local risk factors. However, we detected residual high-risk counties for leptospirosis including counties in the southwest, central, and southeast China. High-risk counties differed from low-risk counties in terms of its demographical, ecological and socioeconomic characteristics. In high-risk clusters, leptospirosis was predominantly observed on younger population, more males and farmers. Additionally, high-risk counties are characterized by larger rural and less developed areas, had less livestock density and crops production, and located at higher elevation with higher level of precipitation compare to low-risk counties. In conclusion, leptospirosis distribution in China appears to be highly clustered to a discrete number of counties highlighting opportunities for elimination; hence, public health interventions should be effectively targeted to high-risk counties identified in this study.