The transcription factor NF-κB is a promising target for chemoprevention. Several dietary plants are efficient inhibitors of NF-κB activation in vitro and could act synergistically on the NF-κB signaling pathway. In this study, we tested whether dietary plant extracts could inhibit NF-κB activation in a synergistic manner in vitro. Second, we investigated the potency of the same dietary plant extracts in the inhibition of NF-κB activation in vivo. A combined extract of clove, oregano, thyme, walnuts, and coffee synergistically inhibited lipopolysaccaride (LPS)-induced NF-κB activation in a monocytic cell line, compared with the sum of effects from the single extracts. Transgenic NF-κB luciferase reporter mice were given a single dose of the combined extract and subsequently challenged with LPS. NF-κB activation was monitored by in vivo imaging for 6 hours. In addition, NF-κB activity in organs and the expression of immune-related genes in liver were investigated. Based on the area under the curve, the extract decreased whole body LPS-induced NF-κB activity the first 6 hours by 35% compared with control mice. Organ-specific NF-κB activation was inhibited in intestine, liver, testis, and epididymis of the mice receiving the combination extract. In addition, dietary plants reduced the expression of genes related to inflammation, cell migration, and proliferation in liver. This study shows that dietary plants may be potent modulators of NF-κB signaling both in vitro and in vivo, and thus support further investigation of consumption of these plant foods as part of a healthy diet or as a mode of chemoprevention.