To evaluate the effect of combining different bioactive root-end filling materials with composite bone graft (xenogeneic mixed with autogenous bone fragments) on the healing process of periapical tissues after endodontic micro-surgery procedure. In this triple-blinded clinical trial, 56 patients were divided into 2 main groups (28 each) according to the root-end filling material and 2 subgroups according to the presence or absence of the composite bone graft material. Group I: MTA root-end filling (n = 28) in which there are Sub-group A: without bone graft (n = 14) and Sub-group B: with composite bone graft (n = 14). Group II: TotalFill root-end filling (n = 28) in which there are Sub-group A: without bone graft (n = 14) and Sub-group B: with composite bone graft (n = 14). Healthy patients whose ages range from 20 to 50 years with small-to-medium size radiolucency in CBCT related to single-rooted maxillary teeth were included in this study. Patients were assigned a number starting from 1 to 56 and were randomly allocated to four test groups (2 main groups and 2 sub-groups) following simple randomization procedure guidelines described by IBM SPSS V23 (IBM USA) statistical analysis software. This trial was triple-blind where the patient, the outcome assessors, and the main operator were blinded to the applied intervention. Every patient was evaluated clinically and by CBCT at two main observation periods: presurgical and 12-month post-operative. They were also examined and evaluated clinically and radiographically through periapical x-rays after one week, three, and six months. Statistical analysis was performed with IBM SPSS Statistics for Windows Version 23.0. Armonk, NY: IBM Corp. Of the 56 patients enrolled in the study, 49 patients were available for the final analysis. All groups showed no statistically significant differences with regard to healing or success rates at the 12-month follow-up mark. No adverse effects were encountered. Results showed that high success rates were achieved using MTA and TotalFill in the healing of periapical lesions after endodontic surgery. The addition of bone graft in small-to-medium size lesions did not affect the success rate of endodontic surgeries.