Tick Borne Encephalitis (TBE) is an acute infectious disease involving central neuropathy caused by the bite of a Tick borne Encephalitis Virus (TBEV) infected tick, which is a typical zoonotic disease. TBE occurs in areas with a wide distribution of tick and its distribution is related to the environment. Besides, it is also a typically natural focus disease in a special ecosystem composed of pathogens, vectors, and host animals. As a natural focus disease, TBE threatens human health and impedes socioeconomic development in northeastern China. Therefore, analyzing the spatial-temporal distribution of TBE and its influencing factors are of vital importance for TBE control. This paper selected Heilongjiang Province, Jilin Province, and the Inner Mongolia Autonomous Region in northeastern China, which are typical TBE endemic areas, to study the spatial-temporal distribution of TBE and its influencing factors. Firstly, we explored the spatial-temporal distribution of TBE in the study area from 2005 to 2015 through statistical analysis and spatial autocorrelation, Secondly, we used Geo-Detector to investigate the factors that influence the spatial distribution of TBE and its indicative role. Our results show that: (1) the incidence of TBE in the endemic areas of Northeastern China had an obvious growth trend and seasonal incidence characteristics from 2005 to 2015. The incidence of TBE in the study area had a strong spatial clustering pattern with two main hot spots, Hulunbuir city in the Inner Mongolia autonomous region and the Greater Khingan Range region in Heilongjiang province; (2) vegetation type, land use, average annual temperature, soil type, average temperature from May to August, slope, elevation, and annual rainfall were the main influencing factors of spatial prevalence of TBE. In general, the influence of natural environment was stronger than that of social environmental; (3) for the whole study area, the relationship between each risk factor and TBE was different, and the incidence of TBE was different with each factor. Besides, the interaction between various factors was significantly enhanced, that is, the impact of two factors was stronger than that of a single factor. The common interaction between some factors exceeded 0.5, and most factors exceeded 0.3. Particularly, the main interaction enhancement effect was manifested in the interaction of each factor with land use and elevation. Our results provide scientific basis and decision support for the effective control of TBE in the study area and the whole country.