Non-enzymatic glycation reaction in food can produce diet-derived advanced glycation end products (dAGEs), which have potential health risks. Thus, it is of great significance to find efficient substances to improve the negative effects induced by dAGEs on human health. This study investigated the intervening effects of peanut skin procyanidins (PSP) on the dAGEs-induced oxidative stress and systemic inflammation in experimental mice model. Results showed that the accumulation of AGEs in serum, liver, and kidney was significantly increased after mice were fed dAGEs (P < 0.05). The expression of advanced glycation product receptor (RAGE) was also significantly increased in liver and kidney (P < 0.05). PSP could not only effectively reduce the accumulation of AGEs in serum, liver and kidney of mice, but also reduce the expression of RAGE in liver and kidney of mice. And the levels of pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and IL-1β in serum of mice were significantly decreased (P < 0.05), while the levels of anti-inflammatory factor IL-10 were increased, and the inflammatory injury in mice was improved. In addition, the levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT) in liver and kidney of mice were increased (P < 0.05), and the level of malondialdehyde (MDA) was decreased (P < 0.05), which enhanced the antioxidant capacity of mice in vivo, and improved the oxidative damage of liver and kidney. Molecular docking technique was used to confirm that the parent compound of procyanidins and its main metabolites, such as 3-hydroxyphenylacetic acid, could interact with RAGE, which might inhibit the activation of nuclear transcription factor (NF-κB), and ultimately reduce oxidative stress and inflammation in mice.