Introduction The extrusion of irrigation solutions beyond the apical constriction may result in postoperative pain. Sodium hypochlorite can cause severe tissue irritation and necrosis outside the root canal system if extruded into the periodontal ligament (PDL) space. Different delivery techniques were discussed to reduce this potential risk. The aim of this study was to compare the postoperative level of pain after root canal therapy using either endodontic needle irrigation or a negative apical pressure device. Material and Methods In a prospective randomized clinical trial, 110 asymptomatic single-rooted anterior and premolar teeth were treated endodontically with two different irrigation techniques. The teeth were randomly assigned to two groups. In the MP group ( n = 55), procedures were performed using an endodontic irrigating syringe (Max-i-Probe; Dentsply Rinn, Elgin, IL). The EV group ( n = 55) used an irrigation device based on negative apical pressure (EndoVac; Discus Dental, Culver City, CA). Postoperatively, the patients were prescribed ibuprofen 200 mg to take every 8 hours if required. Pain levels were assessed by an analog scale questionnaire after 4, 24, and 48 hours. The amount of ibuprofen taken was recorded at the same time intervals. Results During the 0- to 4-, 4- to 24-, and 24- to 48-hour intervals after treatment, the pain experience with the negative apical pressure device was significantly lower than when using the needle irrigation (p < 0.0001 [4, 24, 48 hours]). Between 0 and 4 and 4 and 24 hours, the intake of analgesics was significantly lower in the group treated by the negative apical pressure device (p < 0.0001 [0-4 hours], p = 0.001 [4-24 hours]). The difference for the 24- to 48-hour period was not statistically different (p = 0.08). The Pearson correlation coefficient revealed a strongly positive and significant relationship for the MP group ( r = 0.851, p < 0.001) and the EV group ( r = 0.596, p < 0.0001) between pain intensity and the amount of analgesics. Conclusion The outcome of this investigation indicates that the use of a negative apical pressure irrigation device can result in a significant reduction of postoperative pain levels in comparison to conventional needle irrigation.