Zoonotic diseases are the infectious diseases that can be transferred from vertebrates to humans. Climate changes increase migration of human and animal hosts, vectors, and pathogens and also have considerable impacts on the prevalence of zoonotic diseases. Climatic changes, as well as anthropogenic and natural factors can affect the complicated nature of the human-animal interface. South Khorasan province, located in the Eastern Iran, has dry climate and experiences a very variable climate in the recent years. The current study aimed at evaluating the relationship between climate changes, such as temperature trend and the prevalence of zoonotic diseases in South Khorasan province. Zoonotic infections among residents of all ages in the 11 cities of the province were studied from 2005 to 2014 and were compared with the climate changes (temperature trend); the Pearson test and the geographic information system (GIS) were used to analyze data. The results showed that during the last decade, the emergence of zoonotic diseases dramatically increased, which is of great concern regarding human and animal health. The prevalence of zoonotic diseases showed higher frequencies in the Western part of South Khorasan province, particularly in Tabas and Boshrooye. There were significant differences in the mean annual rate of zoonotic diseases comparing with the mean annual temperature of the province during the studies period (R = 0.74). Assessment of global changes in the status of vector-borne diseases is of great importance, since the risk of zoonotic diseases increases by climate changes due to the proliferation of the hosts, reservoirs, and vectors. Correlation between the changes in zoonotic diseases, occurred in some of zoonotic pathogens in the recent decade in the studied region, and climate indicators showed that climate changes can provide the conditions for endemicity; the condition that did exist before in this region.