In the current study, the soil characteristics, secondary metabolites, and biological activity (antioxidant, antibacterial, and anticancer activities) of four Mediterranean halophytes (Atriplex halimus, Arthrocaulon macrostachyum, Limbarda crithmoides, and Tamarix nilotica) from Egypt were determined. The results showed that the studied halophytes favored soil with a coarse-sandy texture, slightly alkaline, and highly saline, with low contents of organic matter and macronutrients. A. macrostachyum showed the highest concentration of total phenols (181.75 mg GAE g^-1 dry extract) and flavonoids (13.90 mg CE g^-1 dry extract), while T. nilotica had the highest concentration of alkaloids (6.43 mg g^-1 dry extract). Lower contents of soil sulfates, phosphorous, and calcium could induce a greater accumulation of total phenols and flavonoids in these halophytes. The extract of A. macrostachyum exhibited the highest scavenging activity against DPPH (IC₅₀= 0.26 mg/ml) and ABTS (71.16% inhibition). The methanolic extracts of four halophytes exerted a pronounced effect against both Bacillus subtilis and Staphylococcus aureus, while extracts of A. macrostachyum and T. nilotica released an antibacterial effect against Escherichia coli and Pseudomonas aeruginosa. Moreover, A. macrostachyum extract exhibited moderate cytotoxicity against liver hepatocellular carcinoma (HePG2), mammary gland carcinoma (MCF-7), and prostate cancer (PC3). The findings of the current study recommend that the studied halophytes are candidates for green use as food or feed supplements or in various biological applications against antibiotic-resistant bacteria and human cancer cells.