BACKGROUND Leishmaniases are considered a major public health problem in South America, specifically in Brazil. Moreover, the transmission and epidemiology of leishmaniasis are possibly associated with climatic and environmental variations. OBJECTIVE This study aimed to assess the association between the extreme climatic phenomenon El Niño-Southern Oscillation (ENSO), the maximum and minimum variations of temperature, precipitation, and soil moisture and the incidence of visceral leishmaniasis (VL) in Mato Grosso do Sul (MS), Brazil, from 2002 to 2015. METHODS The Niño 3.4 index was used for the ENSO variation. The other climatic data were obtained from the climatic tool TerraClimate. Records regarding VL were obtained from the Notification of Injury Information System. FINDINGS From 2002 to 2015, there were 3,137 cases of VL recorded in MS. The annual incidence of the disease was negatively associated with the ENSO index and soil moisture in MS. The VL incidence increased during the negative phase of ENSO and decreased during the positive phase. MAIN CONCLUSIONS The results demonstrated that the interannual cycles of incidence of human VL are significantly associated with the occurrence of the ENSO phenomenon and its phases, El Niño and La Niña.