Objectives: In this study, we aimed to investigate the therapeutic effects of magnesium sulfate (MgSO4) and dexmedetomidine (dex) in a model of acute lung injury (ALI). We determined whether concomitant administration decreased the inflammatory effects of hydrochloric acid (HCl)-induced ALI in a synergistic manner. Materials and Methods: In this study, 42 Sprague-Dawley rats were randomized into six groups: Group S (saline), Group SV (saline + mechanical ventilation), Group HCl (HCl), Group Dex (Dex), Group Mag (MgSO4), and Group DM (Dex + MgSO4). All groups except Group S were mechanically ventilated prior to HCl-induced ALI. Saline or HCl was administered via tracheostomy. Prior to treatment, HCl was administered to Group HCl, Group Dex, Group Mag, and Group DM to induce ALI. Dex and MgSO4 were administered intraperitoneally. The rats were monitored for 4 h after treatment to measure oxidative stress parameters in blood, and prolidase enzyme activity. Lung tissue damage were determined via histopathology. Results: A significant increase in heart rate and rapid desaturation was observed in HCl-administered groups. Treatment administration decreased the pulse values. Increased saturation values and decreased oxidative stress indices were observed in groups that were subsequently administered Dex and MgSO4. Serum prolidase activity increased significantly in Group HCl. Severe pathological findings were detected following HCl-induced ALI. Group Mag showed greater improvement in the pathology of HCl-induced ALI than did Group Dex. Administration of both Dex and MgSO4 did not improve the pathological scores. Conclusions: The antioxidant and anti-inflammatory effects of Dex and MgSO4 ameliorated the detrimental effects of HCI-induced ALI. However, adverse effects on hemodynamics and lung damage were observed when the two drugs were administered together.