We examined effects of stress, depression, and their interaction on sympathetic-parasympathetic responses, including percentage heart rate (PHR), percentage skin conductance (PSC), percentage finger temperature (PTEMP), and percentage respiratory rate (PRESPR). Participants were categorized into normal, low-risk, and high-risk depression groups under stress or no-stress by measuring psychophysiological responses. Stress increased PHR and PSC and decreased PTEMP. Depression negatively correlated with PHR and PTEMP. PSC and PTEMP were significantly dependent on and positively correlated with depression. PTEMP was significantly affected by the stress and depression interaction. Stress affects sympathetic, rather than parasympathetic, activity. Depression and the interaction between stress and depression initially associated with the sympathetic division and are then correlated with parasympathetic activity. A sympathetic-parasympathetic hypothesis and its clinical implications are discussed.