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Brain tumors and craniotomy surgeries can induce both systemic and neuronal inflammation. Currently, there is a limited amount of literature addressing the influence of anesthetic agents on neuronal and systemic inflammation in neurosurgical settings and its impact on the occurrence of postoperative neurocognitive dysfunction (PND). Our primary objective is to assess the effects of propofol-based total intravenous anesthesia (TIVA) compared to sevoflurane inhalational anesthesia (INHA) with respect to the levels of perioperative inflammatory markers, specifically neuron-specific enolase (NSE) and interleukin-6 (IL-6) in patients undergoing craniotomy for supratentorial tumor surgery. Our secondary objective is to evaluate the correlation of neuronal, systemic inflammatory markers, and the incidence of PND and functional outcomes in patients receiving TIVA versus INHA for supratentorial tumor surgeries. This study protocol details the methodology of a prospective, randomized, and single-center trial approved by the Institutional Ethics Committee and registered with the Clinical Trial Registry of India. The study focuses on patients undergoing craniotomy for supratentorial glioma decompression. Assessing changes in the biomarker level is the primary objective and correlation of this change in biomarker with PND and functional outcome is our secondary objective. The sample size of 45 patients in each group was calculated using n master software by considering alpha of 5%, power of 80%, a mean difference of 79.2 between the groups, and an effect size of 0.603. We describe the study protocol of the single-center trial. The first patient was recruited on September 17, 2023, and we will complete recruitment before March 2025. Our study is expected to inform the impact of anesthesia technique on the biomarkers of the inflammation and consequently PND. Knowledge about this will help the anesthesiologist to select the appropriate anesthetic drug in their clinical practice.