BackgroundSeagrasses are unique marine flowering plants. Enhalus acoroides (L.f.) Royle (family Hydrocharitaceae), a new record for the Egyptian coast of the Red Sea, was the grass of choice. A comparative study on Enhalus acoroides (L.f.) Royle (leaves, roots and rhizomes) was done to determine the plant organ that shows the highest antiproliferative and antioxidant activities. The total phenolic content was determined using the Folin–Ciocalteu method. The total flavonoid content was estimated by the aluminum chloride assay. Fourier transform infrared (FT-IR) analysis was performed to detect the chemical functional groups in the extract. High-performance liquid chromatography (HPLC) was done for the qualitative and quantitative evaluation of phenolic compounds. UPLC-ESI-TOF–MS was performed for metabolomics profiling of the extract. Antioxidant activity was determined using the DPPH scavenger percentage method. Antiproliferation assay against hepatocellular carcinoma HepG2, human breast cancer cell lines MCF-7, MDA-MB-231 was performed for the three seagrass organs. Mitochondrial membrane potential (ΔΨm) was measured after treatment with three extracts against MCF-7 cell line.ResultsThe highest phenolic content is found in the leaves, while roots exhibited the highest DPPH scavenger percentage. The total concentration of phenolic compounds detected by HPLC was leaves > rhizomes > roots. Also leaves exhibit the highest antiproliferative activity and mitochondrial membrane potential depletion effect against MCF-7 cell line tested. UPLC-ESI-TOF–MS metabolite profiling of leaves detected different secondary and primary metabolites to which the activity was retained. Leaves are a new candidate to be used in the treatment of cancer.ConclusionEnhalus acoroides (L.f.) Royle leaves extract is a new nutraceutical candidate. Further in-depth studies are required on Enhalus acoroides (L.f.) Royle leaves.Graphical abstract