Leptospirosis has been recognized as a major public health concern in Thailand following dramatic outbreaks. We analyzed human leptospirosis incidence between 2004 and 2014 in Mahasarakham province, Northeastern Thailand, in order to identify the agronomical and environmental factors likely to explain incidence at the level of 133 sub-districts and 1982 villages of the province. We performed general additive modeling (GAM) in order to take the spatial-temporal epidemiological dynamics into account. The results of GAM analyses showed that the average slope, population size, pig density, cow density and flood cover were significantly associated with leptospirosis occurrence in a district. Our results stress the importance of livestock favoring leptospirosis transmission to humans and suggest that prevention and control of leptospirosis need strong intersectoral collaboration between the public health, the livestock department and local communities. More specifically, such collaboration should integrate leptospirosis surveillance in both public and animal health for a better control of diseases in livestock while promoting public health prevention as encouraged by the One Health approach.