Objective: This study evaluated the effect of Piezosurgery and Trephine bur-assisted cavity preparation techniques on post-operative sequelae including pain, swelling, tenderness to palpation and percussion following guided endodontic microsurgeries. Patients and Methods: Twenty-eight male patients between 18 and 45 years old have mandibular first molar teeth need endodontic microsurgery due to failed non-surgical treatment or re-treatment. The selected patients were randomly divided into two groups (n = 14) according to the type of cutting tools during bony cavity preparation and root end resections. Group I: Piezosurgery assisted cavity preparation. Group II: Trephine Bur assisted cavity preparation. An apical curettage was performed and the over-extended objects such as separated instruments or gutta percha were removed. The postoperative pain and swelling assessment were recorded for five days every 24, 48, 72, 96, and 120 hours postoperatively. The tenderness to palpation and percussion were examined by the operator 3, 6 and 12 months. Results: at the postoperative pain assessment, there was no statistically significant difference between groups. At the postoperative swelling assessment, there was a statistically significant difference between the swelling scores of group I and group II at 72 and 96 hours p= 0.049, 0.043 respectively. The tenderness to percussion and palpation were comparable between the tested groups at 3, 6 and 12 months, there was no statistically significant difference between groups. Conclusion: Piezosurgery-assisted cavity preparation technique improve the postoperative swelling but did not affect the postoperative pain and tenderness to palpation and percussion.