Purpose <p>Chronic craniofacial pain is challenging to treat, with varied outcomes from existing treatments. This study explores the use of an endoscopic transnasal technique for targeting the sphenopalatine ganglion (SPG). The objective was to assess the efficacy and safety of repeated endoscopic transnasal submucosal liposomal bupivacaine (Exparel^®) injections into the SPG for managing craniofacial pain.</p> Methods <p>In this prospective, longitudinal, open-enrollment trial, 11 patients with chronic craniofacial pain were treated at a tertiary center. Patients who experienced symptom relief after an initial bupivacaine challenge were included. Repetitive endoscopic transnasal submucosal SPG blocks (SPGB) with liposomal bupivacaine were then administered in the office under local anesthesia using a spinal needle. Pain was assessed with a 10-item questionnaire at baseline and one day, one week, and one month post-injection.</p> Results <p>Of the 82 injections performed, 81 were successful (98.8%). Analysis of variance showed significant improvements in pain scores for average pain (<i>p</i> &lt; 0.01), worst pain (<i>p</i> &lt; 0.01), and least pain (<i>p</i> &lt; 0.01) in the last 24&#xa0;h at day one and one week post-treatment compared to baseline. Additionally, pain-related quality of life measures, including eating habits, annoyance, and sleep, showed significant improvements (all <i>p</i> &lt; 0.01). Five minor adverse events were reported: transient diplopia (<i>n</i> = 2), headache/facial pain (<i>n</i> = 1), bleeding at the injection site (<i>n</i> = 1), and nasal irritation (<i>n</i> = 1).</p> Conclusion <p>Endoscopic transnasal injection of bupivacaine into the SPG appears to be a safe and effective procedure for providing significant pain relief in patients with chronic craniofacial pain.</p>