The aim of this in-vivo study was to evaluate/compare the clinical periodontal parameters in patients with true combined endo-perio lesions (EPL), treated with gutta-percha (GP) and mineral trioxide (MTA) as an obturation material alone and with addition of bone grafting in such lesions. 120 Saudi patients (mean age = 41yrs) diagnosed with true combined EPL participated in this study. Group I (control group, n = 30) was treated with conventional endodontic treatment using GP for obturation. Group II (n = 30) was treated with conventional endodontic treatment using MTA for obturation. Group III (n = 30) was treated with conventional endodontic treatment using GP for obturation + grafting procedure to fill the bony defect. Group IV (n = 30) was treated with conventional endodontic treatment using MTA for obturation + grafting procedure to fill the bony defect. Clinical parameters (Pocket depth (PD); Clinical attachment loss (CAL); keratinized tissue width (KTW); gingival phenotype (G.Ph.) and Cone Beam Computed Tomography Periapical Index (CBCTPAI)) were recorded and compared at baseline, 3, 6, 12 months' interval. For the groups III and IV, CBCTPAI showed significant difference (p < 0.0001) with the other groups at 6 months and 1-year interval. The group with MTA + bone graft showed 76% and 90% patients with 0 score at 6 months and 1-year follow-up, respectively. Comparison of mean values of PD among study groups at 3 months, 6 months and 1 year showed significant difference at 3 months, whereas the mean PD values of subjects in GP + bone graft showed significantly higher PD values than other 3 groups (p = 0.025). Use of GP and MTA for root canal obturation along with periodontal therapy and bone augmentation helps in resolving complex endo-perio lesions. Bone grafting in addition to obturation with MTA was found to be the best treatment strategy in management of EPL cases and is recommended for clinicians who are treating EPL patients.