Sulfur hexafluoride (SF 6) gas leakage in populous urban areas, once occurring, can cause death from suffocation if its concentration largely exceeds 1000ppm and oxygen concentration is low than 19 vol-%. Leakage that cannot be detected and responded to with prompt and effective measures can even lead to large death tolls. Presently, few systematic technical approaches to monitoring, early-warning, consequence prediction, and emergency response of SF 6 leakage have been reported. In this paper, a method for constructing the early-warning and emergency response system for SF 6 leakage in substations is proposed. Firstly, the concentration distribution of leaked SF 6 gas at different leakage points within the substation space is analyzed using CFD simulation to determine the coordinates of sensitive areas where the exceeding of the threshold value of SF 6 concentrations is first detected and thus to ascertain sensor monitoring points. By altering leakage locations and leakage orifice diameters within the substation space, the data concerning the coupling relationship between leakage time, leakage orifice diameter, and concentration are obtained, and a prediction model of diffusion concentration of SF 6 leakage in substations is established through regression. Based on the prediction model, an emergency response system for SF 6 leakage in substations is constructed; additionally, in combination with safety management data of substations, the files required for emergency responses to SF 6 leakage can be identified immediately after occurrence, which provide a guidance for on-field personnel to take emergency responses and safety prevention measures. In this paper, a case study of a substation leakage event is presented to describe the method to construct an early-warning and emergency response system for leakage in substations, as well as the application of the method. The results of this research can provide a theoretical basis for early-warning and emergency response to SF 6 leakage, thereby improving the inherent safety levels of substations.