This article put forward a theoretical system, which is used to analyze co-optimization of CO2 sequestration and enhanced oil recovery by using the methods or theories including the design of experiments, numerical simulation, net present value, and the response surface methods. A CO2 flooding operation in an immiscible water-alternating-gas process of Shanbei extra-low permeability reservoir was estimated preliminarily by using the methods proposed in this article. The result shows that optimized values obtained from predicted values were in good agreement with the values obtained from the simulation model and it is possible to optimize a coupled CO2 sequestration and enhanced oil recovery project.