The purpose of this clinical trial was to compare post-operative pain levels following the first stage of two-visit emergency endodontic treatment in patients with either an intermediate-acting local anesthetic (2% lidocaine with 1:100,000 epinephrine) or a long-acting local anesthetic (0.5% bupivacaine with 1:200,000 epinephrine). Twenty-one patients in need of emergency non-surgical endodontic treatment were included in this study. The first stage of two-visit nonsurgical root canal treatment was performed, and patients were asked to report their post-operative pain levels until the end of the following day using Categorical Scales, Visual Analog Scales, and Heft Parker Scales. A trend was observed where post-operative pain levels reported by patients receiving bupivacaine were lower in the first 12 hours when compared with patients who received lidocaine. During the following day, no additional analgesic effects were observed for patients who received long-acting local anesthetics. Male patients who received bupivacaine reported less post-operative pain than females who received bupivacaine. The trends observed in this study suggest that long-acting local anesthetics are effective in the management of post-operative pain, and that males may benefit more than females from the analgesic effects of long-acting local anesthetics.