Soy protein is an important component of soybeans that has beneficial role in improving insulin resistance. Nuclear factor kappa B (NF-κB) is a crucial pathway that has been implicated in the development of metabolic syndrome. Our study aimed to examine the protective effect of soy protein isolate - as a natural NF-κB inhibitor - and its possible mechanism of action in amelioration of inflammatory and metabolic disorders induced in male albino rats by high fructose diet (10% w/v) via using synthetic NF-κB inhibitor (IMD-0354). Rats were randomized into normal control group, soy group, NF-κB inhibitor (IMD-0354) group, high fructose group, high fructose with soy group, high fructose with NF-κB inhibitor group, high fructose with soy and NF-κB inhibitor group. Serum glucose, serum insulin, serum free fatty acids, insulin resistance (HOMA-IR), NF-κB, phosphorylated insulin receptor (pISR), carbohydrate-responsive element-binding protein (ChREBP) were determined and histopathological examination of liver tissue was performed. The concurrent administration of IMD-0354 and/or soy protein with high fructose significantly increased pISR and decreased FFAs, NF-κB, glucose, insulin, HOMA-IR, and ChREBP as well as improved the pathological conditions of the livers. The metabolic and inflammatory disorders induced by chronic consumption of fructose could be inhibited by co-administration of soy protein through regulation of NF-κB signalling pathway.