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The increasing number of antibiotic-resistant bacteria necessitates the development of natural antimicrobial substances with minimal health risks. Medicinal plants’ antimicrobial effects are becoming more well known around the world. Mangroves are biochemically distinctive in that they create a wide range of novel natural compounds, including steroids, triterpenes, saponins, flavonoids, alkaloids, and tannins. Plants from the mangrove family have long been utilized in medicine. Ethanol was used to make a plant extract of Sesuvim portulacastrum in this investigation. Some antibiotic-resistant and harmful bacterial and fungal species were investigated for antimicrobial activity. The extract was evaluated at different concentrations (25, 50, 75, and 100 µL). As inhibition zones, the 100 µL concentration produced the best results. The inhibition zones of Sesuvium portulacastrum L. plant extract ranged from 8 mm to 18 mm against the majority of microorganisms tested. The highest effect was against Aspergillus niger, whereas the least was against Staphylococcus aureus, according to the findings. Sesuvium portulacastrum L. extract contains tannins, alkaloids, glycosides, flavanoids, and terpenoids, according to the qualitative phytochemical study. The current investigation found that Sesuvium portulacastrum L. extract has a significant antimicrobial impact against a number of diseases.