The research aim was to test the Job Demand–Control (JDC) Model demands × Control interaction (or buffering) hypothesis in a simulated bus driving experiment. The buffering hypothesis was tested using a 2 (low and high demands) × 2 (low and high decision latitude) design with repeated measures on the second factor. A sample of 80 bus operators were randomly assigned to the low (n = 40) and high demands (n = 40) conditions. Demands were manipulated by increasing or reducing the number of stops to pick up passengers, and decision latitude by imposing or removing restrictions on the Rapid Transit Bus (BRT) operators’ pace of work. Outcome variables include physiological markers (heart rate [HR], heart rate variability [HRV], breathing rate [BR], electromyography [EMG], and skin conductance [SC]), objective driving performance and self-report measurements of psychological wellbeing (psychological distress, interest/enjoyment [I/E], perceived competence, effort/importance [E/I], and pressure/tension [P/T]). It was found that job decision latitude moderates the effect of job demands on both physiological arousal (BR: F(1, 74) = 4.680, p = .034, SC: F(1, 75) = 6.769, p = .011, and EMG: F(1, 75) = 6.550, p = .013) and psychological well-being (P/T: F(1, 75) = 4.289, p = .042 and I/E: F(1, 74) = 4.548, p = .036). Consistently with the JDC model buffering hypothesis, the experimental findings suggest that increasing job decision latitude can moderate the negative effect of job demands on different psychophysiological outcomes. This finding is useful for designing organizational and clinical interventions in an occupational group at high risk of work stress-related disease.