Background: This study aimed to monitor the effects of subgingival application of Methods: Eighty participants with stages 2 or 3 (moderate to severe) periodontitis were included, comprising individuals with partially controlled and uncontrolled (HbA1c >7%) type II diabetes as well as nondiabetic subjects, were randomly divided into four groups (20 in each group) by using the sealed opaque envelope method. They received different treatment modalities: root surface debridement (RSD) combined with either ALV gel or chlorhexidine (CHX) gel. Periodontal parameters and blood samples were obtained at baseline and after 3 months to estimate levels of glycated hemoglobin (HbA1c), PGE2, interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and IL-6. Results: ALV gel demonstrated a significant effect on the improvement of clinical periodontal parameters, including plaque index (PI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level. It also significantly reduced levels of PGE2, fasting blood sugar (FBS), HbA1c, and pro-inflammatory cytokines after 3 months of therapy in both diabetic and nondiabetic periodontitis patients ( Conclusions: ALV gel exhibits a similar effect to CHX in reducing and improving clinical periodontal parameters, blood sugar levels, PGE2, and cytokine levels. Therefore, ALV gel can be administered locally as an adjunct to RSD in diabetic patients with chronic periodontitis.