Objectives: Titanium platelet-rich fibrin (T-PRF) usage as sustained drug delivery system (SDDS) has been recently started. Hence present study aimed to evaluate hard tissue regenerative efficacy of T-PRF clots incorporated with amoxiclav (AMX)/metronidazole (MET)eem (NE) gels individually in osseous defects created in Wistar rats. Materials and Methods: In this in vivo animal model trial, 12 female Wistar rats were procured and subjected to ligature induced periodontitis.Bone defects were created and incorporated with T-PRF plain, T-PRF clots+AMX/MET/NE gels individually. Rats were sacrificed after 2 months and checked under light microscopy and micro (µ)-computed tomography analysis for bone regeneration. Frequency distribution percentages, chi-square test, ANOVA and un-paired t-test were used for conducting the statistical analysis. Results: Inflammatory response was reported in T-PRF+MET Group followed by AMX Group and no inflammatory response was recorded for T-PRF plain with statistical significance (P=0.008), for mineralized and un-mineralized bone formation there was no significant difference (P=0.133). Mean comparisons of bone density there was no significant difference (P=0.545) among all (AMX=551.00±18.68, MET=578.00±18.25, NE=569.00±24.58, T-PRF plain=507.67±118.50). For gene expression significantly (P<0.001) higher alkaline phosphatase and bone morphogenetic protein-2 levels were recorded for T-PRF+NE Group (7.60±3.04, 10.85±1.28) followed by MET (4.65±1.52, 4.64±0.45)>AMX (2.47±0.84, 1.89±0.18)>T-PRF plain (1.00±0.00, 1.00±0.00). Conclusion Research results showed that T-PRF can be a SDDS and addition of antibiotics or herbal extract didn’t alter the hard tissue healing property of T-PRF and resulted in new bone formation.