Background: The efficacy of manual carotid artery compression in reducing cerebral embolization during cardiac surgeries is a topic of debate. Aim: This study aimed to assess the safety and efficacy of carotid artery compression in preventing postoperative cognitive dysfunction (POCD) in patients undergoing mitral valve replacement surgery. Methodology: This randomized, double-blind, parallel-group clinical trial enrolled 120 adult patients scheduled for mitral valve replacement surgery. The patients were randomly assigned to two groups of 60 patients each. Group C underwent carotid artery compression using three fingers (index, middle, and ring fingers) along the path of the artery for 20 seconds following aortic declamping, while group NC did not undergo carotid artery compression. The study's primary outcome was the incidence rate of POCD at 5-7 days and the Mini-Mental State Examination score. Secondary outcomes included the incidence rate of POCD after 6 weeks postoperatively and transcranial Doppler readings. Results: The incidence rates of POCD at 5-7 days and after 6 weeks postoperatively were comparable in both groups (p=0.163 and 0.364, respectively). Additionally, the Mini-Mental State Examination score and transcranial Doppler results were comparable between the groups before and after surgery. The incidence of cognitive dysfunction in the NC group at 5 days postoperatively was significantly associated with older age, shorter surgical duration, and reduced middle cerebral artery velocity by transcranial Doppler. Conclusion: Carotid artery compression does not prevent cognitive dysfunction after mitral valve replacement surgery. However, no additional harm is associated with carotid compression.