Background Stress response always occurs in cardiac valve replacement patients undergoing cardiopulmonary bypass (CPB). Methods 60 patients undergoing cardiac valve replacement were recruited and randomized into control and Dex groups. Dex group received 1.0 μg·kg-1 of Dex for 10 min intravenously before anesthesia, followed by 0.5 μg·kg-1·h-1 of Dex, steadily administered throughout the procedure. And controlled group received the identical velocity of saline as Dex group. Plasma level of cortisol (Cor), epinephrine (E), norepinephrine (NE), and serotonin (5-HT) were evaluated at four timepoints: Before administration (T0), sawn sternum (T1), end of extracorporeal circulation (T2), and 24 h post operation (T3). General data of operation and recovery such as heart rate (HR), mean arterial pressure (MAP), intraoperative bispectral index (BIS), and hospitalization time in the intensive care unit (ICU) were also compared. Results Increase of Cor, E, NE, and 5-HT for the Dex group was significant lesser than that in the control group (P < 0.05), and ICU hospitalization time and ventilator support time was significantly shorter in the Dex group. The proportion of patients discharged from the hospital with better prognosis was significantly higher than that in the control group, while there were no significant differences in hospitalization costs and vasoactive drugs use between the two groups. Conclusions Dex reduces plasma Cor, E and NE elevations in patients after CPB, alleviates the stress reaction of the body, shortens the hospitalization time and ventilator support time in ICU, and plays a positive role in the rehabilitation of patients undergoing cardiac valve replacement. Trial registration China Clinical Trial Registry (No. ChiCTR-IPR-17010954) March 22rd, 2017.