2-isoprenylhydroquinone-1-glucoside (1), 3,5-dicaffeoylquinic acid (2), and 3,5-dicaffeoylquinic acid methyl ester (3), isolated from Phagnalon rupestre, improved the contact hypersensitivity response to 2,4,6-trinitrochlorobenzene in mice. These phenolics reduced ear swelling and IL-1β content by 50% 24 h after challenge; in addition, 2 inhibited tumor necrosis factor-α by 53%. All three compounds also reduced interleukin-2 content by 50% 72 h after challenge. Both 2 and 3 inhibited metalloproteinase-9 levels in the skin lesions by 66% and 41%, respectively, and lowered cyclooxygenase-2 expression by 44% and 49%, respectively, at 24 h. Moreover, 2 was effective against atopic dermatitis induced by repeated application of 2,4,6-trinitrochlorobenzene; it attenuated edema by over 40% from day 7 and inhibited inflammatory cell infiltration by 44% at day 22. In addition, 1-3 reduced metalloproteinase-9 expression in a dose-dependent manner in macrophages RAW 264.7 stimulated with lipopolysaccharide. Thus, compounds 2 and 3 were found to exhibit a greater activity against contact hypersensitivity than 1.