Chlorhexidine gluconate (CHX) is widely recognized as the gold standard for chemical plaque control; however, its use is associated with certain side effects. Alternatively, sesame oil (Sesamum indicum) has shown promising results in reducing plaque through the traditional method of oil pulling. Despite its increasing popularity, limited data exists on the comparative cytotoxic effects of CHX and sesame oil. This study aims to evaluate and compare the anti-plaque, anti-gingivitis, and cytotoxic effects of CHX mouthwash and Sesamum indicum oil pulling in individuals with chronic generalized gingivitis. A double-blind clinical trial will be conducted in the Department of Public Health Dentistry, Government Dental College and Hospital, Ahmedabad, over a period of 3–4 months. A total of 75 participants will be randomly divided into three groups: CHX mouthwash, sesame oil pulling, and control. Clinical parameters will be assessed using the Turkesky Gilmore Glickman modification of the Quigley-Hein Plaque Index and the Loe and Silness Gingival Index at baseline and after 21 days. Cytological evaluation will be done through buccal mucosa cell collection and micronucleus assay to assess genotoxic effects. Statistical analysis will be performed using SPSS v27, with a significance level set at 5%. It is expected that while CHX may demonstrate superior efficacy in reducing plaque and gingival inflammation, it may also exhibit higher cytotoxicity compared to Sesamum indicum oil.