Bioassay-directed fractionation of an antioxidant methanol extract of the leaves of Chrozophora senegalensis using DPPH assay led to the isolation of three new flavonoid glycosides, quercetin 3-O-(6″-caffeoyl)-β-D-glucopyranoside-3′-O-β-D-glucopyranoside (1), quercetin 3-methyl ether-7-O-α-L-rhamnopyranosyl-(1→6)-(2″-p-coumaroyl)-β-D-glucopyranoside (2), acacetin 7-O-(6″-p-coumaroyl)-β-D-glucopyranoside (3), along with five known flavonoids, one phenolic derivative, and three megastigmane glycosides. Their structures were established on the basis of detailed spectral analysis. All isolated compounds were tested for their antioxidant activity on DPPH stable radical, superoxide anion, metal chelating activity, and DNA cleavage induced by the photolysis of H₂O₂. Quercetin 3-O-(6″-caffeoyl)-β-D-glucopyranoside-3′-O-β-D-glucopyranoside (1), quercetin 3′-methyl ether-3-O-α-L-rhamnopyranoside (4), and 4″'-methyl ether amenthoflavone (9) exhibited the highest antioxidant capacity being also able to modulate hydroxyl radical formation more efficiently than other compounds acting as direct hydroxyl radical scavengers and chelating iron.