Calligonum polygonoides L. subsp. comosum (Polygonaceae) is a wild shrub that grows on the sandy deserts of various regions in North Africa, Western Asia and Southern Europe. In some of Asian countries, the flower buds and young branches of the plant are used to prepare traditional food dishes. Also, different organs of C. polygonoides L. are used traditionally in treatment of stomach diseases. The isolation of anti-inflammatory lead compounds was performed by using different normal silica gel, reversed phase C-18, and sephadex LH-20 open columns. The identification of the isolated compounds was done using NMR spectral techniques. The isolated compounds are of different flavonoid classes; two flavonol glycosides; kaempferol-3-O-β-D-glucuronide and mequilianin, one flavan-3-ol; catechin, and one dihydro-flavonol; taxifolin. The methanol extract and ethyl acetate fraction of Calligonum polygonoides L. subsp. comosum exhibited anti-inflammatory activity against NF-κB translocation pathway on HEK293 cells. All of them were active against NF-κB translocation, and previously isolated from the plant under study. Kaempferol-3-O-β-D-glucuronide, a flavonoid glycoside demonstrated the most potent NF-κB inhibition in comparing with other flavonoids; taxifolin, catechin, and mequilianin. Therefore, the food plant aerial parts of C. polygonoides are rich in nutraceuticals (flavonoids and flavonoid glycosides) that can be utilized in the treatment of vascular inflammation.