Evaluation of local indigenous medicinal rice (Oryza sativa Linn.) varieties using molecular and metabolic profiling plays dynamic role for unravelling the genetic variability and restorative bio actives. In the present study, 18 screened random decamer (RAPD) markers were used to analyze genetic diversity and relationship among 25 indigenous landraces and 1 commercial rice varieties (White ponni), and GC-MS profiling of phylogenetic clusters positioned 4 random indigenous rice varieties and 1 White ponni rice were documented for exploring bioactive metabolites. Random amplified polymorphic DNA (RAPD) analysis of twenty-six rice varieties of Tamil Nadu divulges significant genetic differentiation. The primers produced total of 92 bands with size ranges from 100-8500bp out of 74 were polymorphic bands indicating 80% polymorphism. The mean values of RAPD for polymorphism information content (PIC) of 0.268, effective multiple ratio (EMR) of 23.38, marker index (MI) of 7.39 and the resolving power (Rp) of 4.34. The primer OPA-02, OPD-08, OPF-13 produced maximum number of bands (8), OPAA-07 produced minimum number of band (2). The UPGMA dendrogram were constructed based on Jaccard’s similarity coefficients. The dendrogram resolved the indigenous rice varieties into 3 main clusters and 3 monoclades ranged from 0.467 to 0.860, commercial rice variety shows marginal ungrouped position of 1. In the 3-main clustering, based GC-MS profilling (methanol and acetone rice bran extracts) of Karuppu Kavuni, Karuthakar, Kottara samba, Kaivara samba and ungrouped position of White ponni revealed 88 distinctive bioactive metabolites. And profiling results substantiate that the traditional rice varieties hold promising therapeutic metabolites for sedentary lifestyle disorders.