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The Ayurvedic principle “Yatha Dravya Tatha Guna” emphasizes that the therapeutic efficacy of a substance is determined by its intrinsic qualities (Guna) and actions (Karma) rather than its external form or nomenclature. In the present era, increasing scarcity of medicinal plants due to overexploitation, habitat destruction, and environmental changes poses significant challenges to the continuity of traditional therapeutic practices. Within this context, the Ayurvedic concept of Abhav Pratinidhi Dravya, or substitute drugs, provides a systematic and rational framework to ensure uninterrupted treatment while preserving therapeutic integrity. The objective of this study is to critically analyze the philosophical foundation of drug substitution in Ayurveda and to examine its conceptual compatibility with modern pharmacological principles. The study is based on a comprehensive review of classical Ayurvedic literature, including authoritative texts such as Bhavaprakasha, Yogaratnakara, and Bhaishajya Ratnavali. The criteria for substitution were examined through the lens of Rasapanchaka, encompassing Rasa, Guna, Virya, Vipaka, and Prabhava, along with their clinical relevance and therapeutic outcomes. In addition, modern scientific perspectives were incorporated by considering parameters such as phytochemical similarity and pharmacological validation using analytical techniques like TLC,HPLC and HPTLC. The findings indicate that classical Ayurvedic substitution primarily depends on the similarity of Karma and Rasapanchaka rather than botanical identity. Several traditional substitutions demonstrate remarkable therapeutic equivalence, such as the use of Shatavari as a substitute for Meda owing to comparable Rasayana properties, and Cyperus rotundus as an accessible alternative to Aconitum heterophyllum. Contemporary pharmacological evaluation supports these substitutions through the identification of comparable bioactive compounds, reinforcing the scientific plausibility of traditional practices.In conclusion, the concept of Abhav Pratinidhi Dravya plays a crucial role in ensuring therapeutic reliability, patient safety, and ecological sustainability. The integration of Ayurvedic principles with modern pharmacological validation highlights the relevance of substitution as a rational, evidence-informed approach to addressing the global scarcity of genuine medicinal resources. This convergence of ancient wisdom and modern science offers a sustainable pathway for the continued application of Ayurvedic therapeutics in contemporary healthcare.