Naturally sourced products like propolis are commonly employed for the non-surgical treatment of periodontal pockets. The use of nanoparticle formulations of these natural remedies has the potential to improve treatment outcomes. The aim of the present study was to evaluate the efficacy of sub-gingivally delivered propolis nanoparticles in the non-surgical management of periodontal pockets. Forty patients diagnosed with periodontitis presenting at least one periodontal pocket with a probing pocket depth between 4 and 6 mm were selected. Patients were randomly assigned into the control group (n = 20), which received scaling and root planing (SRP) and saline (SRP + Saline), and the test group (n = 20), which received SRP and sub-gingivally delivered propolis nanoparticles (PRO) into the periodontal pocket (SRP + PRO). The clinical parameters recorded were plaque index (PI), gingival index (GI), relative attachment loss (RAL), probing pocket depth (PPD), and bleeding on probing (BOP). They were assessed at baseline, one month, and three months post therapy. The results indicated that there was a significant improvement in clinical parameters (p p value of p values of 0.0001, 0.001, and 0.05, respectively. The subgingival delivery of propolis nanoparticles showed promising results as an adjunct to SRP in patients with periodontitis presenting periodontal pockets.