Background: Non-availability, indefinite identity, and adulteration of medicinal plants are key worrying areas in herbal or natural product-based industry/market. In this regard, the approach of ancient physicians does not seem to be hypothetical or haphazard. They had applied their mind and laid down certain principles and also evolved a methodology to identify and adopt substitutes. Abu Bakr Mohammad Ibn Zakariya al-Razi (Rhazes) (865–925 AD), a leading physician of Unani System of Medicine and Persian scholar of the early Islamic world compiled an exclusive monograph entitled as “Maqala Fi Abdal al-Adwiya al-Mustamala Fi al-Tibb wa al-Ilaj” popularly known as “Kitab al-Abdal” which is the first and foremost unique book on substitutes of Drugs in Unani Medicine. Aims and objective: This review aims to explore the rationality for substitution of the drugs mentioned by Rhazes in view of fundamental principles of Ayurveda. Materials and methods: All the 223 substitutes of 122 original drugs mentioned in the transcript of “Kitab al-Abdal” have been thoroughly scrutinized and categorized accordingly as per the adopted fixed criteria (i.e., Category I: Single substitutes for an original drug, Category II: Double substitutes for an original drug, Category III: Triple substitutes for an original drug, Category IV: Tetrad/four substitutes for an original drug). Any drugs or substitutes, which are not available in Ayurveda texts, were excluded from the analysis. Result and discussion: Analyzed data highlight that about 76% substitutions are having similarity with fundamentals of Ayurveda (Rasapañcaka) and Unani Medicine (Yaksaniyat-e-mizaj). Although the maximum substitutes mentioned in “Kitab al-Abdal” are not practiced or directly mentioned in the texts of Ayurveda as a source of substitute/alternative source of the particular original drug, but the rationales behind the substitution are often similar with the fundamental concept of Ayurveda (Rasapañcaka). The review may serve as ready references for the researcher, physicians, as well as industry of both Ayurveda and Unani system of medicine in order to find the appropriate substitution of a rare raw drug. This may also confess the scope of multidimensional research for harmonization of unique substitution and their inclusion in the National Pharmacopeia.