BackgroundOral health is crucial for overall well-being, and periodontal disease can lead to serious complications such as intraosseous defects. In recent years, local administration of 1% melatonin gel has been explored as a potential treatment option for intraosseous defects. However, its efficacy compared to traditional non-surgical periodontal therapy (NSPT) is not fully understood.Primary Study ObjectiveTo evaluate and compare the efficacy of 1% melatonin gel local administration with non-surgical periodontal therapy (NSPT) in the treatment of stage I and stage IV periodontal bone defects.Methods/DesignOne hundred participants diagnosed with stage I and stage IV periodontal disease were recruited from Hangzhou Younuo Dental Clinic between December 2020 and March 2022. The participants were divided into two groups: a study group and a control group. The study group received local administration of 1% melatonin gel, while the control group received non-surgical periodontal therapy (NSPT). Oral examinations, including X-ray examinations, were conducted to assess the severity of bone defects before treatment initiation. The primary outcome measures included treatment efficacy, periodontal indicators (PD and BI levels), inflammatory response indicators (IL-1β, IL-6, and TNF-α levels), bone defect heights, and alveolar bone densities.ResultsThe treatment efficacy in the study group was significantly higher than that in the control group (95% CI -3.0 to -1.8, P = .011). Post-treatment, the study group had lower PD and BI levels compared to the control group (95% CI -1.0 to -0.8, P < .001; 95% CI -1·2 to -0.7, P < .001). Post-treatment, the study group had lower levels of IL-1β, IL-6, and TNF-α compared to the control group, (95% CI 0.3 to -0.8, P < .001; 95% CI -4.1 to -2.1, P < .001; 95% CI -3.5 to -1.6, P < .001). Post-treatment, the study group had lower bone defect heights and higher alveolar bone densities compared to the control group (95% CI 0.7 to 1.1, P = .028; 95% CI -2.2 to -1·8, P < .001).ConclusionLocal administration of 1% melatonin gel may be an effective treatment option for improving bone defects, enhancing periodontal indicators, alleviating inflammatory responses, and improving oral health in patients with stage I and stage IV periodontal disease.