Objective: Stress and glucocorticoid drugs disrupts the hypothalamic-pituitary-adrenal axis that is one major causes of depression. The benefits of probiotics may extend to systems beyond the gastrointestinal tract; i.e. the central nervous system. Thus, a synbiotic (probiotic+prebiotic) mixture effect was investigated on dexamethasone (Dex) and stress induced depression. Methods: Male albino mice were used, the forced swimming test (FST) measured despair, while sucrose preference test measured anhedonia. The synbiotic regimen (12.5 × 10 6 CFU) was inserted in drinking water for 7 days. Dex was administered subcutaneously either single-dose on the test day or for 7 days. Water avoidance stress (WAS) induction, 1 hour each day for 4 days. Results: Drinking synbiotic reduced the immobility time during FST (54±7 sec vs, 111±6 sec water group, p<0.001). Dex injection significantly increased the immobility time (single-dose=166±6 sec, and 7 day=174±9 sec) compared to the control groups, while adding synbiotic to their drink reduced it (single dose= 81 ± 6.6 sec, and 7 days= 84 ± 14 sec), indicating that synbiotic reversed Dex induced depression. WAS increased immobility time (148±11 sec, vs sham 99±6 sec, p<0.001) in FST test, by adding the synbiotic treatment following WAS, the immobility time decreased (81 ± 6.5 sec).The synbiotic groups also had a higher percentage of sucrose preference. Conclusion: The synbiotic mixture prevented the effects of WAS, acute or sub-acute Dex induced depression in mice. Therefore, probiotics might be useful and safe supplements to prevent depression related to stress or glucocorticoid therapies that deserves further evaluation.