Abstract: In order to realize high quality and efficiency utilization of energy while improving the reliability of system energy supply, the concept of exergy is introduced into regional integrated energy system containing a high proportion of renewable energy, and a two-layer optimization method is proposed considering exergy efficiency and multiple uncertainties. Firstly, a multi-energy coupling model of regional integrated energy system is established for exergy and multi-uncertainties analysis. Multi-scene random planning and range optimization methods are adopted to deal with exergy for different characteristics of solar and wind power uncertainty, along with load and energy price fluctuations. Then, a two-layer collaborative optimization model balances system capacity planning and scheduling operations is constructed, with both exergy efficiency and economy as the optimization goal in the upper layer, and the lowest operating cost as the optimization goal in the lower layer. Finally, an industrial park is selected for example analysis to verify the effectiveness of the proposed method in this paper. Compared with other uncertain factors, the fluctuation of electrical load has a greater impact on the economy and exergy efficiency of the system.