Background: Dexmedetomidine and Fentanyl have both been used as adjuvant to prolong the effect of local anesthetics in various peripheral nerve blocks. The primary aim of this study was to compare these two in scalp nerve block for obtunding pain response to skull pin insertion. The secondary aim was to study their effect on post-operative pain relief, time required for extubation and post-operative sedation score. Methodology: A total of 80 American Society of Anesthesiologists’ physical status Grade 1 and 2 patients between 18 to 60 years, electively posted for supratentorial craniotomy for space occupying lesion, were randomly divided into two groups to receive either Dexmedetomidine 1 µg/kg (Group D) or Fentanyl citrate 1 µg/kg (Group F) added to 20 ml of 0.25% Bupivacaine in bilateral scalp nerve block, 10 minutes before May field pin insertion. Hemodynamic parameters were assessed at regular time intervals and time taken for extubation after surgical closure was noted. Post-extubation pain scores and sedation scores were assessed periodically and time taken for first rescue analgesic was also noted. The observer was blinded to randomization, preparation of drug syringes and statistical analysis. Chi-square test, Fischer-exact test, Post-hoc tukey test and student’s t-test were used for analysis. Results: Requirement of propofol was significantly lower in Group D than Group F, (p = 0.013) one minute after pin insertion. Hemodynamic variables, Extubation time and sedation scores were comparable in both groups. Pain-free period was longer in Group D, (p = 0.045). Conclusion: Addition of dexmedetomidine as adjuvant to local anesthetic in scalp nerve block provides superior attenuatation of hemodynamic response to skull pin insertion and prolongation of analgesia than Fentanyl used for the same purpose.