Human-related factors are a crucial inducement of traffic accidents. Understanding the influence of freeway environments on the driving behavior and workload experienced by drivers has been demonstrated to be of primary importance for improving traffic safety. To study the effect of alignment, traffic flow, and sign information on drivers’ mental workload and behavior, 16 scenarios were constructed using the orthogonal design method, and simulated driving experiments were carried out with 45 participants. During driving, indicators such as the mean and standard deviation of vehicle speed and lane departure were collected, and the NASA-TLX questionnaire was adopted to measure workload. Analysis of variance results indicated that the radius of the horizontal curve, gradient, flow, and sign information level have a significant influence on drivers’ workload and speed keeping ability. In addition, the horizontal curve radius has a significant effect on lane keeping ability. The importance of safety influencing factors on driving workload and performance was quantitatively ranked by integrating the trend of Deng’s correlation degree, comprehensive correlation degree, and similar correlation degree, whose weight was calculated using the entropy method. Traffic sign information was found to have the greatest impact on workload. In terms of driving performance, traffic volume has the greatest influence on the mean and standard deviation of vehicle speed, followed by the amount of sign information. Lane departure is most affected by the radius of the horizontal curve. These findings provide guidance for freeway traffic safety regulation, including workload control and road facility optimization.