In order to study the change law of the fatigue degree of grassland expressway drivers over time, this paper takes the semidesert grassland landscape of Xilinhot city as the experimental environment and takes the provincial highway S101 (K278–K424) as an example to design an actual driving test. Taking Urumqi, Inner Mongolia Autonomous Region, as the experimental section, combined with the Biopac MP150 multichannel physiological instrument and its auxiliary knowledge software and mathematical statistics methods, the relationship between EEG and time was studied. The test results show that the primary fatigue factor F1 and the secondary fatigue factor F2 can summarize the fatigue law characterized by 96.42% of EEG information. During 130 minutes of driving on the prairie highway, the periods of high fatigue were 105 minutes and 125 minutes, respectively. Driving fatigue can be divided into three stages over time: 5–65 min fatigue-free stage, 70–85 min fatigue transition stage, and 90–130 min fatigue stage. Fatigue changes over time. The law follows the Gaussian function and the sine function.