This study aims to evaluate the effect of Nd:YAG laser therapy (NdLT) on postoperative pain, swelling, and trismus after mandibular third molar (M3) surgery. Three hundred patients were randomly divided into the Nd group ( n = 100), medication group ( n = 100), and Nd+medication (Nd+m) group ( n = 100). The WHARFE classification system was used to assess surgical difficulty. After surgery, the Nd group was irradiated by the Nd:YAG laser in very long-pulsed mode (VLP, pulse duration 1 ms, 20 Hz, 4 W, R21-C3) in 6 regions of the extraction socket with a total energy of 300 J. For the medication group, dexamethasone 0.75 mg and loxoprofen 60 mg were prescribed immediately and every 12 h thereafter for 3 days. The Nd+m group received both treatments mentioned above. Pain assessment was performed at 6, 24, 48, and 72 h postoperatively using the visual analog scale (VAS). Swelling was evaluated by changes in the distance from (1) the tragus to the labial commissure, (2) the tragus to the pogonion, and (3) the mandibular angle to the lateral canthus preoperatively and 72 h postoperatively. Trismus was assessed by the change in maximum mouth opening. Groups Nd and Nd+m had lower VAS scores at 6 h, 24 h, and 48 h ( F = 13.80, p = 0.00), but the difference between the two groups was not significant ( F = 1.34, p = 0.11). However, no significant difference was observed at 72 h ( p = 0.10). There was no significant difference in swelling or trismus among the three groups ( p > 0.05). NdLT is an effective approach to improve complications after M3 surgery.