Objectives The aim of this study was to compare the effects of mineral trioxide aggregate (MTA) and platelet-rich fibrin (PRF) use on periapical healing in surgically treated periapical lesions using three-dimensional (3D) cone-beam computed tomographic (CBCT) imaging. Materials and methods A total of 40 periapical lesions undergoing apical surgery were selected between December 2016 and November 2017. The participants were randomly divided into four study groups: control, MTA, PRF, and MTA+PRF. No interventions were made in the control group except root-end resection. Routine radiographs were taken in the 3rd, 6th, and 12th months. The volume and density of periapical lesions at the 1-year follow-up were compared with the pre-op values using the MIMICS software program. Primary healing of the periapical tissues was evaluated, and the outcomes were noted. Results Post-op volume values were significantly decreased, and density values were significantly increased according to the pre-op measurements. In the post-op volume evaluation between the groups, significant differences were observed in the MTA and MTA+PRF groups compared with the control group (p < 0.005). However, no substantial significance was noted between the control and PRF groups. There were no significant differences in post-op density calculations between all groups. Trial registration number: NCT03743987 (The Effect of MTA and PRF Application in Periapical Lesions).