BACKGROUND Non-surgical periodontal therapy (NSPT) is the cornerstone of periodontitis management. This comparative clinical study evaluates the effectiveness of three different non-surgical treatment approaches in three treatment groups, namely, Quadrant-wise Scaling and Root Surface Debridement (Q-Sc + RSD), Full-mouth Disinfection (FMDis), and Full-mouth Debridement (FMDeb). METHODS A total of 45 patients with generalised stage II and III periodontitis were randomly assigned to one of the three treatment groups. Plaque scores (PS), bleeding scores (BS) and probing pocket depths (PD) were recorded at baseline and post-NSPT. Data were analyzed to compare the changes in PS, BS, and PD distribution at baseline and post-NSPT in all three groups. RESULTS All three treatment approaches resulted in statistically significant reductions in PS, BS, and PD distribution compared to baseline. However, FMDeb and FMDis protocols demonstrated greater reductions in BS and PD distribution compared to the Q-Sc + RSD protocol. Remarkably low BS were observed in all three study groups at the post-treatment evaluation, with statistically significant differences compared to their respective pre-treatment BS. CONCLUSIONS All three treatment approaches were effective in reducing PS, BS, and PD in patients with periodontitis, while FMDeb and FMDis protocols demonstrated superior effectiveness in terms of reduction of BS and PD, compared to the Q-Sc + RSD protocol. Further research with larger sample sizes and longer follow-up periods may be warranted to confirm these findings and evaluate the long-term clinical outcomes of these different debridement approaches of NSPT. BACKGROUND The UK's Clinical Study Registry ISRCTN13350022, 28/05/2025, retrospectively registered.