Five Salsola species have been studied as sources of bioactive compounds using a comprehensive, untargeted metabolomic and bioactivity assessment. Plant material was extracted using ethyl acetate (EA), water, and methanol (MeOH). S. ruthenica exhibited the highest total phenolic content (46.04 mg GAE/g, MeOH extract) and antioxidant capacity (DPPH: 47.21 mg TE/g; ABTS: 97.40 mg TE/g; CUPRAC: 141.38 mg TE/g; FRAP: 80.30 mg TE/g). Extracts of S. stenoptera and S. ruthenica showed potent cholinesterase inhibition, while S. crassa was notably active against tyrosinase. A total of 265 metabolites were annotated, revealing strong solvent- and species-specific differences in phenolic composition, as confirmed by AMOPLS analysis. Flavanols, anthocyanins, and lignans emerged as the major chemotaxonomic markers, based on PCA, contributing the most to the total variance. Strong correlations were observed between TPC and CUPRAC (r = 0.93) and between flavanols and DPPH (r = 0.70), suggesting functional relevance of these compounds in redox activity, confirming the importance of different classes of phenolic constituents. VIP markers also revealed species- and solvent-specific enrichments of metabolites. Regularized canonical correlation analysis (rCCA) further linked specific metabolites, namely Quercetin 3-O-glucosyl-xyloside and 6″-O-Acetylgenistin, the flavanone sakuranetin, the lignans Secoisolariciresinol, Anhydro-secoisolariciresinol, and Medioresinol, and p-Coumaric acid ethyl ester, with antioxidant functions. These findings underscore the pharmacological potential of Salsola species and highlight the importance of valorizing metabolic diversity in the search for new sources of health-promoting natural compounds. Furthermore, the work shows the need for a tailored solvent selection in bioactivity-guided phytochemical research.