The aim of this study was to investigate the effect of saponin fraction (SF) from red ginseng on obesity-induced inflammatory response in a co-culture system of 3T3-L1 and RAW264.7 cells. HPLC analysis showed that SF contains more than 50% ginsenosides, and Rb1 was the most abundant ginsenoside [135.31 μg/mg (extract)]. The production of nitric oxide and cytokines, induced by adipocyte-conditioned medium (3T3-CM), was significantly decreased by SF. SF (100 μg/mL) suppressed the abundance of tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) by 78%, 40%, and 22%, respectively. This SF-mediated reduction in inflammatory cytokines was due to the suppression of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation, and translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) into the nucleus. SF also regulated adipokine expression in adipocytes, which were stimulated by macrophage-conditioned medium (RAW-CM); adiponectin expression was upregulated (> 2-fold), while resistin was downregulated (40%). In the contact system of adipocytes and macrophages, SF significantly decreases MCP-1 (37%) and IL-6 (25%) production. In the transwell system, SF (100 μg/mL) significantly increased the abundance of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein, hemoxygenase-1 (HO-1) by 1.5∼3.5-fold and 2.8∼3.6-fold, respectively, thus increasing Nrf2 translocation into nucleus. However, SF-mediated inhibitory effect on the release of IL-6 and MCP-1 cytokines was reversed in the Nrf2 or HO-1 knockdown condition. This result indicated that SF-mediated inhibition of obesity-induced inflammation was dependent on Nrf2 activation.