Background: Calligonum polygonoides is an endemic plant species, belongs to Polygonaceae family, native to the "Thar Desert" of India. It is highly tolerant to multiple stresses with dominant biomass and phytochemical producer under extreme niche. It has significant ethnopharmacological applications, but not yet scientifically validated. Materials and Methods: The methanolic extract of C. polygonoides flower bud was subjected to gas chromatography mass spectroscopy (GC-MS) analysis and antioxidant potential assay was done on different radical scavenging scales. The phytochemicals were identified based on retention time and matching their mass spectra to spectra in NIST 14 library. Results: The results revealed the presence of fatty acids, phenolics, terpenoides, flavanoids, alkaloids, tannins, steroids, ketones, esters, and amino acid derivatives, which comprises 93 compounds. Most of the detected compounds have been proved to possess important bio-activities such as anti-microbial, anti-inflammatory, anticancer, anti-diabetic, hepatoprotective, cardiovascular, antioxidant, and antimutagenic. Interestingly, some compounds such as furan-2,5-dimethyl, 2,3-dihydro-2,5-dihydroxy-6 -methyl-4H-pyran-4-one (DDMP), dehydromevalonic lactone, deoxyspergualin, 2-methoxy-4-vinylphenol, benzeneethanol-4-hydroxy-, quinic acid, lauric acid, linolenic acid, and squalene were detected which have proved pharmaceuticals applications against major diseases such as cancer, diabetics, cardiovascular, and some other chronic diseases. Furthermore, the methanolic extract also attributed very high level of antioxidant potential on cupric reducing antioxidant capacity, ferric reducing antioxidant power, 2,2-diphenyl-1-picrylhydrazyl, and phosphomolybdenum assay scales. Conclusion: The identified phytochemicals with ample pharmaceutical application explore the worthiness of this endemic plant species. Along with pharmaceutical, it has an immense scope in nutraceutical and functional food industry. These medicinal importance advised for its conservation and artificial regeneration, to sustain the agro-ecological balance of Thar Desert of India.