Aim: To evaluate and compare the effectiveness of nanocrystalline hydroxyapatite (NcHA) with advanced platelet-rich fibrin (A-PRF) and hydroxyapatite-reinforced beta tricalcium phosphate (HA + β-TCP) with A-PRF in the treatment of human infrabony defects clinically and radiographically using cone-beam computed tomography (CBCT). Materials and methods: There were a total of 28 defects, with 14 defects in the test and control groups, respectively. There were total 28 patients were involved in the study. The test group (group A) was treated with NHA and A-PRF, while the control group (group B) was treated with HA + β-TCP and A-PRF. Bone defect fill was the primary result of the investigation. Periodontal pocket depth (PPD), R-CAL, papillary bleeding index (PBI), and PI were the secondary outcome. Clinical and radiographic measurements were recorded at baseline and 6 months postoperatively. Results: No significant difference was observed between the two groups in terms of PPD reduction (4.64 ± 0.74 mm vs 4.07 ± 0.99 mm), clinical attachment loss (CAL) gain (4.64 ± 0.74 mm vs 3.92 ± 0.99 mm) and radiographic defect depth reduction (2.41 ± 0.32 mm vs 2.40 ± 0.27 mm) for test and control groups, respectively. Conclusion: At 6-month post-surgery, both treatment modalities demonstrated statistically significant improvements with regard to CAL gains, PPD reduction, and reduction in radiographic defect depth. Clinical relevance: The NcHA and HA + β-TCP with A-PRF is a novel material used in the treatment of infrabony defect for periodontal regeneration. The NcHA and HA + β-TCP with A-PRF need to consider biomaterials for bone defect fill.