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The current study aimed to investigate the phytochemical contents and antioxidant, antimicrobial, and antibiofilm activities of four halophytic plants, namely, <i>Euphorbia chamaesyce</i>, <i>Bassia arabica</i>, <i>Fagonia mollis</i>, and <i>Haloxylon salicornicum</i>, native to central Saudi Arabia. The alcoholic extract of <i>E. chamaesyce</i> was found to be the most potent in various bioactivities-based evaluations and rich in polyphenols and flavonoid secondary metabolites, with 68.0 mg/g and 39.23 mg/g gallic acid and quercetin equivalents, respectively. Among all plants’ extracts, the alcoholic extract of <i>E. chamaesyce</i> had the highest DPPH scavenging and metal chelating antioxidant activities at 74.15 Trolox equivalents and 16.28 EDTA equivalents, respectively. The highest antimicrobial activity of <i>E. chamaesyce</i> extract was found to be against <i>Shigella flexneri</i>, with a mean zone of inhibition diameter of 18.1 ± 0.2 mm, whereas the minimum inhibitory concentration, minimum biocidal concentration, minimum biofilm inhibitory concentration, and minimum biofilm eradication concentration values were 12.5, 25, 25, and 50 mg/mL, respectively. The LC-ESI-MS/MS analysis of the <i>E. chamaesyce</i> extract showed the presence of six flavonoids and ten phenolic constituents. The in silico binding of the <i>E. chamaesyce</i> extract’s constituents to <i>Staphylococcus aureus</i> tyrosyl-tRNA synthetase enzyme displayed −6.2 to −10.1 kcal/mol binding energy values, suggesting that these constituents can contribute to the antimicrobial properties of the plant extract, making it an essential medicinal ingredient. In conclusion, these results warrant further investigation to standardize the antimicrobial profiles of these plant extracts.