Background <p>Various techniques are being used to create a relatively bloodless surgical field during endoscopic trans-sphenoidal pituitary gland surgery (ETS). Pterygopalatine fossa (PPF) block helps to improve the field of surgery and control haemodynamic fluctuations.</p> Methods <p>Eligible patients with the American Society of Anaesthesiologists class I or II were randomly classified by closed envelope method. Group TN received bilateral transnasal PPFB with 4 mL of 0.25% bupivacaine after induction of general anaesthesia. Group PC received bilateral ultrasound-guided infrazygomatic percutaneous PPFB with the same dosage and timing.</p> Results <p>A total of 60 patients were included and randomized into the two groups. Between the two groups, there was no statistically significant difference in mean arterial blood pressure (MABP) and heart rate (HR). Fentanyl and dexametomidine were less significantly used intraoperatively in the PC group. Total intraoperative isoflurane consumption and the mean consumption per minute used intraoperatively were significantly higher in TN group (<i>p</i> &lt; 0.001). Regarding Boezaart surgical field grading was no statistically significant difference between Group TN and Group PC at any time point.</p> Conclusion <p>Ultrasound-guided percutaneous PPF block offers superior efficacy in reducing intraoperative anaesthetic consumption and opioid use compared to the transnasal approach in endoscopic transsphenoidal pituitary surgery. This technique contributes to enhanced haemodynamic stability and a more efficient anaesthetic management profile during surgery.</p> Trial registration <p>Clinicaltrials.gov. Identifier NCT06836583, 24 February 2025.</p>