Objective: To assess and compare the effects of epidural xylazine (XY), magnesium sulphate (MG) and their combination (XY-MG) in buffalo. Design: Crossover study Animals: Seven healthy, non-pregnant buffalo Procedures: Buffaloes were allocated into one of three groups in a prospective randomized crossover design with two weeks washout period as the following: XY group, MG group and XY-MG group. The sedative, analgesic, and behavioral effects of XY, MG and their combination were evaluated prior to administration and at then after injection at 5, 10, 15, 30, 45, 60, 90 120, 150, 180, and 210 minutes. Results: Clinical and hematological variables were evaluated at baseline (0 minute) and then at 15, 30, 45, 60, 90, 120, 180, and 210-minutes post-administration. Buffaloes received XY-MG combination showed the fastest onset and resulted in the longer duration of epidural analgesia. The longest duration of complete sedation was recorded in group XY-MG. All treatment protocols caused mild ataxia and affected the heart rate, respiratory rate and rectal temperature of buffalo. There was a significant decrease in the blood glucose at 30 minutes after injection in all groups, returning to the baseline level by 180 minutes in XY-MG group and 210 minutes in XY and MG groups. Conclusion and clinical relevance: XY-MG combination may be used as epidural sedative and analgesic to control pain in buffalo.