Oman has a long coastline (~ 3, 165 km) with special environmental attributes such as high salinity (range between 35.5 to 40 PSU), elevated temperatures, high light intensity, and limited nutrients. During monsoon (Kareef), the southern part of Oman (especially Dhofar province) experiences one of the biggest upwelling phenomena worldwide, which brings with it high levels of nutrients, high waves, and colder water temperatures, which influence the quality and composition of seaweed ingredients. In addition, a comprehensive list of seaweeds in Oman showed 402 taxa, including several species reported worldwide as potential sources of valuable ingredients, such as carrageenan, agar, alginate, fucoidan, pigments, etc. Although the worldwide production of seaweed has increased in response to the rise in demand, the full potential of Omani seaweeds has not yet been studied. This study will open the door for more intensive research in this field. Brown (Phaeophyceae), red (Rhodophyta), and green (Chlorophyta) are the main categories of seaweed. Seaweed (multicellular autotrophic organisms) classification is based on pigmentation content. Seaweeds are valuable sources of bioactive compounds in biomedicine, cosmetics, food, and pharmacology. This study aimed to determine the chemical composition, as well as bioactive and antimicrobial properties of organic solvent extracts of the two red seaweed species Melanothamnus somalensis & Gelidium omanense, and the two brown seaweed species Jolyna furcate & Nizamuddinia zanardinii collected from the southern part of Oman (Dhofar Province). Five organic solvents (hexane, dichloromethane, ethyl acetate, acetone, and methanol) were used sequentially to achieve extraction. The chemical composition included approximate composition, mineral profile, and protein quality; whereas characterization work of the extracts included total phenolic content (TPC), total flavonoid content (TFC), and total tannin content (TTC). The antimicrobial investigation included several bacterial strains (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus) and one fungal strain (Candida albicans) that are of global health concern. There were significant variations detected in the chemical composition, TPC, TFC and TTC. The brown seaweed, Jolyna furcate showed high protein, lipid, and carbohydrate contents compared to Nizamuddinia zanardinii. However, Nizamuddinia zanardinii showed high ash and moisture contents. Jolyna furcate showed higher mineral content, especially sodium, potassium calcium and magnesium beside all macro-elements (hydrogen, nitrogen, and carbon). Furthermore, Jolyna furcate had higher TPC in all fractions except the acetone fraction. Except with dichloromethane, TFC in the other solvents’ extracts was high in Nizamuddinia zanardinii. In all fractions, Jolyna furcate had high TTC. The red seaweed Gelidium omanense showed high moisture, lipid, and carbohydrate compared to Melanothamnus somalensis. However, Melanothamnus somalensis showed high ash and protein contents compared to Gelidium omanense. Melanothamnus somalensis showed higher mineral content, especially sodium and potassium. Furthermore, Melanothamnus somalensis had higher TPC in all fractions except the hexane fraction. Except with hexane, TFC in the other solvents’ extracts was significantly different between Gelidium omanense and Melanothamnus somalensis. There were no significant differences in TTC in all fractions, except dichloromethane and ethyl acetate fractions. In addition, almost all samples in this study were free of heavy metals so they could be used as food supplements for essential minerals and organic materials according to recommended doses. Only the methanol extract of Nizamuddinia zanardinii (MeNZ) showed interesting antimicrobial activity; the inhibition zone was 13 ± 1 mm. Furthermore, MeNZ was fractionated, and fraction 1 (MeNZ-F1) was recognized to have antimicrobial activity; the inhibition zone was 14.66 ± 0.57 mm. Stock concentration revealed higher activity against microbes in comparison with diluted ones at three hours of incubation. TEM and SEM results showed that E. coli treated with the active fraction had an irregular shape and rough surface, and leakage of cellular content was observed. Furthermore, ribosomes were clustered and directed toward the inner membrane of the bacteria, and the DNA clustered in the center of the cell. Both seaweeds had high TPC, TFC, and TTC when compared with other seaweeds, and this is in part because of the use of several solvents for extraction. Both seaweeds were deficient in one or more of the essential amino acids. In addition, all samples in this study were free of heavy metals so they could be used as food supplements for essential minerals and organic materials according to recommended doses. In addition, the methanol extract of Nizamuddinia zanardinii had good efficiency against pathogenic bacteria and fungi. Therefore, it can be a noble constituent for the improvement of antimicrobial drugs in the food and pharmaceutical industries.