INTRODUCTION: Neuroinflammation, neuronal cytotoxicity, and apoptosis due to exposure to anaesthetic agents are often implicated in postoperative cognitive dysfunction (POCD). Lidocaine and dexmedetomidine have been shown to suppress the neuron-specific markers of inflammation, and we aimed to compare their neuroprotective efficacy in elderly patients. MATERIAL AND METHODS: This prospective randomized control study compared the incidence of POCD in ASA I/II patients aged 60 to 80 years without any history of substance abuse or any disorder affecting cognition. Dexmedetomidine and lidocaine were administered intraoperatively, and their effects on POCD were correlated with serum levels of IL-1, IL-6, TNF-a, amyloid-β, and S100 on postoperative day 3. POCD was assessed by the Stroop test, Trail making test-B, Porteus Maze test, Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA) on the day before surgery and the third postoperative day, along with blood samples. RESULTS: Demographic parameters, anaesthesia duration, exposure to anaesthetic gases, intraoperative opioid use, and blood transfusion were similar in the lidocaine ( n = 31) and dexmedetomidine ( n = 29) groups. The incidence of POCD was 29.03% in the lidocaine group and 24.1% in the dexmedetomidine group ( P = 0.77). On postoperative day 3, IL-1 levels increased by 449% with lidocaine and 202% with dexmedetomidine ( P = 0.03). TNF-a, IL-6, and S-100β levels increased similarly in both groups. There was no significant correlation between percentage changes in neuropsychological tests and biomarkers. CONCLUSIONS: There was no significant difference in the incidence of POCD, but dexmedetomidine had a better anti-inflammatory effect in terms of lesser rise of postoperative IL-1 compared to lidocaine.