OBJECTIVES: To evaluate the effect of coconut oil on the oral bacteriome and inflammatory response in patients with periodontitis by integrating next-generation sequencing analyses of pathogenic bacterial shifts and quantification of inflammatory markers, thereby assessing its potential as a natural adjunct to standard nonsurgical periodontal therapy. MATERIALS AND METHODS: A triple-blind clinical trial was conducted with 30 participants diagnosed with periodontitis, randomized into 3 groups: (1) coconut oil, (2) chlorhexidine and (3) placebo. Saliva and gingival crevicular fluid (GCF) samples were collected before treatment, one month after treatment, and one month post-non-surgical periodontal therapy. Bacterial DNA was extracted, and the V3-V4 region of the 16 S rRNA gene was PCR-amplified and sequenced using Illumina MiSeq technologies. Inflammatory biomarkers, including Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), were quantified from GCF samples. RESULTS: Coconut oil treatment significantly reduced pathogenic bacterial families such as Spirochaetaceae and Tannerellaceae while promoting beneficial bacteria such as Streptococcaceae. At the genus and species levels, coconut oil reduced pathogens such as Tannerella forsythia and Treponema denticola along with increase in beneficial bacteria such as Streptococcus. The subgingival microbial dysbiosis index improved significantly in both coconut oil and chlorhexidine groups. Furthermore, the coconut oil demonstrated a reduction in IL-6 and TNF-α levels, indicating decreased local inflammation. CONCLUSIONS: Coconut oil treatment significantly modulated the oral microbiome and reduced inflammatory markers in patients with periodontitis, suggesting its potential as a natural and effective adjunct in periodontal therapy. CLINICAL RELEVANCE: This study highlights coconut oil's potential as a natural adjunct in periodontal therapy, effectively reducing pathogenic bacteria and inflammatory markers (IL-6, TNF-α). It offers a safe alternative to chlorhexidine, promoting microbiome balance and improved periodontal health.