The present study was designed to investigate the bioactive compounds in extracts of Rumex vesicarius L. (Polygonaceae), a wild edible herb growing in Egypt. Ethyl acetate and n-butanol fractions of leaves of R. vesicarius were conducted by HPLC-PDA-MS/MS-ESI in the negative mode to analyze phenolics content. Results revealed the identification of 13 phenolic compounds: 8-C-glucosyl-apigenin, 8-C-glucosyl-luteolin, 6-C-hexosyl-quercetin, 3-O-rutinosyl-quercetin, 7-O-rhamno-hexosyl-diosmetin, 7-O-rhamno-acetylhexosyl-diosmetin, catechin, epicatechin, ferulohexoside, 6-C-glucosyl-naringenin, epicatechin gallate, 6-C-glucosyl-catechin, and epigallocatechin gallate. Quantification of the identified compounds revealed that 6-C-glucosyl-naringenin was the major compound. Also, qualitative and quantitative analysis of the hydro-ethanolic extract of leaves was carried out for ascorbic acid, α-tocopherol, β-carotene. The essential oil as well as lipids analysis of saponifiable and unsaponifiable matters. The biochemical studies were conducted to evaluate the antioxidant and hepatoprotective potential of roots (REE), leaves (LEE), and fruits (FEE) ethanolic extracts of R. vesicarius (100 mg/kg b.wt., p.o., each) against hepatotoxicity induced by CCl(4) (0.5 mL/kg b.wt., p.o., 3 times a week) compared with silymarin (50 mg/kg b.wt., p.o.) as standard drug. The results confirmed that coadministration of the tested extracts or silymarin with CCl(4) for 4 wk exhibited a marked hepatoprotective activity, attributed to their antioxidant potential, membrane stabilizing effect, and antifibrogenic activities. Practical Application: Investigation of the effect of hommad as a safe hepatoprotective diet that prospectively directs the attention to a valuable therapeutic natural herb rich in bioactive constituents.