We reviewed a case of bilateral sphenopalatine ganglion (SPG) blockade with liposomal bupivacaine for sinus surgery. The case was complicated by severe postoperative hypertension refractory to antihypertensives and needing intensive care unit (ICU) admission. While SPG blockade has been used to treat headaches and provide perioperative analgesia, this complication and a possible mechanism have not been described. We discuss how local anesthetic spread beyond the SPG may have caused prolonged parasympathetic blockade and hypertension. Before approved indications are established, we recommend avoiding the use of liposomal bupivacaine in off-label settings when the function of bilateral autonomic structures could be affected.