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Introduction: Breast cancer is the most common type of cancer globallyand its treatment with many FDA-approved synthetic drugs manifests various sideeffects. Alternatively, phytochemicals are natural reserves of novel drugsfor cancer therapy. Punica granatum commonly known as pomegranate is arich source of phytopharmaceuticals. Methods: The phytoconstituentsof Punica granatum leaves were profiled using GC-MS/MS in the presentwork. Cytoscape-assisted network pharmacology of principal and prognosticbiomarkers, which are immunohistochemically tested in breast cancer tissue, wascarried out for the identification of protein target. Followed by, rigorousvirtual screening of 145 phytoconstituents against the three ER isoforms(α, β and γ) was performed using Discovery Studio. Thedocked complexes were further evaluated for their flexibility and stability usingGROMACS2016 through 50 ns long molecular dynamic simulations. Results: In the current study, we report the precise and systematic GC-MS/MS profiling ofphytoconstituents (19 novel metabolites out of 145) of hydromethanolic extractof Punica granatum L. (pomegranate) leaves. These phytocompounds arevarious types of fatty acids, terpenes, heterocyclic compounds and flavonoids.4-coumaric acid methyl ester was identified as the best inhibitor of ER isoformswith drug-likeness and no toxicity from ADMET screening. γ-ligandbinding domain complex showed the best interactions with minimum RMSD, constantRg, and the maximum number of hydrogen bonds. Conclusion: We conclude that 4-coumaric acidmethyl ester exhibits favourable drug-like properties comparable to tamoxifen, anFDA-approved breast cancer drug and can be tested further in preclinical studies.