Oxidative and inflammatory damage have been suggested to play important roles in the pathogenesis of diabetic nephropathy (DN). Chlorogenic acid (CGA) is one of the most abundant polyphenols and has known immunoprotective, antioxidant and anti-inflammatory properties. In the present study, animal experiments were designed to examine the protective effects of CGA in DN, and cellular experiments were designed to explore the underlying mechanisms. CGA significantly attenuated diabetic renal damage based on histological pathology and molecular biological methods. Pre-treatment with CGA increased the nuclear translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) and reduced the phosphorylation of IκB and subsequent nuclear translocation of nuclear factor kappa beta (NF-κB). Nrf2 small interfering RNA (siRNA) and the HO-1 inhibitor zinc protoporphyrin (ZnPPIX) significantly increased the nuclear translocation of NF-κB and the production of pro-inflammatory cytokines in HBZY-1 cells. The NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) increased Nrf2 nuclear translocation and HO-1 expression and antioxidant levels. Thus, these results suggest that CGA is a potential therapeutic agent in the treatment of DN due to its antioxidant and anti-inflammatory effects which are mediated via the modulation of the Nrf2/HO-1 and NF-κB pathways. Moreover, CGA-induced the activation of Nrf2/HO-1,which interacts with the inhibition of NF-κB, as each begets and amplifies the other.