Cyber-attacks against the cyber–physical power system (CPPS) may lead to major power outages and even system collapse in severe cases. In order to quantify the attack losses and select optimal strategies to defend against cyber-attacks, this paper proposes a computational model of integrated cyber–physical losses based on the theory of interdependent network. Based on the multiple coupling relationship between cyber system and physical network, the monitoring system is regarded as the cyber–physical interaction layer, and the information network operation constraint, physical system load reduction constraint, and monitoring equipment operation constraint are established respectively to analyze the impact on another network after a failed node appears in one layer of network, and proposed the cyber–physical integrated loss objective function. The offensive and defensive processes are abstracted into a two-player zero-sum game model, which evolves into a multi-stage game according to the changes in the system state during the game, and the integrated cyber–physical loss is used as the game gain of both the attacker and defender, and the Minimax-Q algorithm is introduced to solve for the optimal gain and select the optimal defense strategy. Finally, the IEEE 30 node cyber–physical system is used as a simulation example to verify whether the proposed loss calculation model can effectively quantify the losses caused by the attack on the information network and the power grid, and has practical guidance for the selection of the optimal defense strategy.