A prominent security threat to unmanned aerial vehicle (UAV) is to capture it by GPS spoofing, in which the attacker manipulates the GPS signal of the UAV to capture it. This paper introduces an anti-spoofing model to mitigate the impact of GPS spoofing attack on UAV mission security. In this model, linear regression (LR) is used to predict and model the optimal route of UAV to its destination. On this basis, a countermeasure mechanism is proposed to reduce the impact of GPS spoofing attack. Confrontation is based on the progressive detection mechanism of the model. In order to better ensure the flight security of UAV, the model provides more than one detection scheme for spoofing signal to improve the sensitivity of UAV to deception signal detection. For better proving the proposed LR anti-spoofing model, a dynamic Stackelberg game is formulated to simulate the interaction between GPS spoofer and UAV. In particular, for GPS spoofer, it is worth mentioning that for the scenario that the UAV is cheated by GPS spoofing signal in the mission environment of the designated route is simulated in the experiment. In particular, UAV with the LR anti-spoofing model, as the leader in this game, dynamically adjusts its response strategy according to the deception’s attack strategy when upon detection of GPS spoofer’s attack. The simulation results show that the method can effectively enhance the ability of UAV to resist GPS spoofing without increasing the hardware cost of the UAV and is easy to implement. Furthermore, we also try to use long short-term memory (LSTM) network in the trajectory prediction module of the model. The experimental results show that the LR anti-spoofing model proposed is far better than that of LSTM in terms of prediction accuracy.