Climate changes have a profound effect on human health, especially when infectious diseases are concerned. Variable factors including temperature, precipitation, and relative humidity directly influence the magnitude and frequency of water-borne pathogen transfers. In this study, we determined the long-term temporal trends and seasonal patterns of shigellosis and evaluated the effects of demographic and climatic factors on its incidence in Yazd province, Iran, during 2012 through 2015. The incidence of shigellosis was highest among patients in the age group of 6–20 years and peaked in every summer of the years studied, especially during August. Furthermore, there was a significant association between climatic variables (such as monthly temperature, humidity, and atmospheric dust) and the incidence of shigellosis. However, contrary to expectations, rainfall did not affect incidence of the disease. The transmission of Shigella to humans is a complex ecological process. Socio-economic factors and lifestyle behaviours need to be addressed in future studies.