The study monitored physiological parameter changes after 120-min of simulated driving. Blood pressures, heart rate (HR), heart rate variability (HRV) and palm temperatures were measured using an ANSWatch((R)) monitor. Subjects were divided into two groups (A & B). Both groups performed 2-hour driving, but group B additionally took a 15-min exercise break. Heart rate, systolic pressure, LF/HF, and palm temperature decreased for group A after driving; for group B only HR and palm temperatures decreased. HRV and parasympathetic indices HF(AU) and HF(NU) increased for group A, while HRV and sympathetic index LF(AU) increased in group B. Group A had higher fatigue scores than group B. ANS activation may overcome some fatigue symptoms, but the recovery is nonetheless incomplete. Exercise break is proven to be an effective remedy, especially if accompanied by the ANS actions. The normalized parasympathetic index HF(NU), the normalized sympathetic index LF(NU), and the sympatho-vagal balance index LF/HF are three most promising parameters that could be further developed to monitor driver fatigue.