Background: Chronic periodontitis (CP) is a prevalent inflammatory condition leading to the progressive destruction of periodontal tissues. Non-surgical periodontal therapy (NSPT), often combined with systemic antibiotics, is an effective treatment for CP. This study aimed to compare the effectiveness of Azithromycin versus Amoxicillin/Metronidazole in reducing probing pocket depth (PPD) and bleeding index (BI) following NSPT in chronic periodontitis patients. Methods: A randomized controlled trial was conducted with 60 patients diagnosed with chronic periodontitis. These participants were randomly assigned to receive either Azithromycin (500 mg per day for 3 days) or a combination of Amoxicillin (500 mg) and Metronidazole (400 mg), administered three times a day for 7 days, alongside non-surgical periodontal therapy (NSPT). Clinical outcomes, specifically probing pocket depth (PPD) and bleeding index (BI), were assessed at baseline and again 3 months post-treatment. Statistical analyses included paired t tests for intra-group comparisons and independent t-tests for inter-group differences. Results: Both treatment groups showed significant reductions in PPD and BI at 3 months. However, the Azithromycin group demonstrated a more significant reduction in PPD (mean reduction: 3.5 mm vs. 2.9 mm, p < 0.05) and BI (mean reduction: 1.3 vs. 1.0, p < 0.05) compared to the Amoxicillin/Metronidazole group. Conclusion: when combined with NSPT, Azithromycin showed superior clinical outcomes compared to Amoxicillin/Metronidazole in treating chronic periodontitis. Azithromycin can be a more effective adjunctive treatment for improving periodontal health post-NSPT.