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Introduction: Panchakarma, the fivefold Ayurvedic therapeutic detoxification regimen, has been traditionally employed to restore doshic balance and enhance systemic homeostasis. Recent research suggests that lifestyle interventions, dietary practices, and therapeutic procedures may influence gene expression via epigenetic mechanisms. This review explores the potential role of Panchakarma in modulating epigenetic markers and its implications for health and disease prevention. Methods: A systematic literature review was conducted using PubMed, Scopus, Web of Science, Google Scholar, and the AYUSH Research Portal. Classical Ayurvedic texts (Charaka Samhita, Sushruta Samhita, Ashtanga Hridaya) were also analyzed. Studies published between 2000–2025 evaluating Panchakarma or Ayurvedic interventions in the context of gene expression, DNA methylation, histone modifications, or microRNA regulation were included. Clinical trials, observational studies, experimental models, and in vitro analyses were reviewed. Results: Evidence indicates that Panchakarma therapies may influence oxidative stress, inflammatory pathways, and metabolic homeostasis, all of which are known to impact epigenetic regulation. Experimental studies suggest modifications in DNA methylation patterns, histone acetylation, and microRNA profiles following detoxification, herbal interventions, and lifestyle integration. Clinical observations demonstrate improvements in biomarkers associated with inflammation, metabolic syndrome, and oxidative stress, potentially reflecting epigenetic modulation. Discussion: Panchakarma may represent a non-pharmacological strategy to favorably modulate epigenetic mechanisms, bridging traditional Ayurvedic wisdom with modern molecular biology. While preliminary data are promising, limitations include small sample sizes, heterogeneous interventions, and limited mechanistic studies. Future research integrating multi-omics approaches is warranted. Conclusion: Panchakarma shows potential in influencing epigenetic pathways, suggesting a scientific basis for its long-observed rejuvenative and preventive effects. Rigorous trials and molecular studies are necessary to elucidate its role in precision health interventions.

KEYWORDS: Ayurveda, Detoxification, Epigenetics, Panchakarma, Rejuvenation