ABSTRACT Background Abdominal sepsis patients suffer from profound intravascular fluid deficit due to concomitant inflammatory response and capillary leakage. It is reported that anti-inflammatory properties of sedative agents can control inflammatory cascade in many experimental septic conditions. We aimed to investigate the best sedative drug for inflammatory responses and capillary leak in patients with abdominal sepsis. Methods In this prospective randomized study, 60 patients with abdominal sepsis who underwent abdominal surgery and required post-operative sedation and mechanical ventilation were randomized into 3 groups in a 1:1:1 ratio. Group D (sedated with dexmedetomidine), group P (sedated with propofol), and group M (sedated with midazolam). This study was held in intensive care units of Assiut University Hospitals with primary outcome was serum IL-6 and IL-1β. Secondary outcomes were capillary leak index, lactate clearance, vasopressor requirements, total intake, total output, and fluid balance. Results Dexmedetomidine significantly reduced levels of IL-6 and IL-1β through 48 hours compared to both midazolam and propofol. Dexmedetomidine caused a significant decline in capillary leak index (p < 0.05) through 48 hours and significant higher lactate clearance (p = 0.03) in first 24 hours compared to both midazolam and propofol. Dexmedetomidine group had a significantly lower intake in first 24 hours and comparable vasopressor requirements through 48 hours. Dexmedetomidine group had a significantly higher output, lower serum creatinine levels and lower positive fluid balance compared to propofol and midazolam. Conclusions Dexmedetomidine reduced inflammatory response and capillary leak in mechanically ventilated patients with abdominal sepsis with better lactate clearance and less fluid intake.