The aim of the present study was to clarify whether oxidative stress and inflammatory responses are related to impaired insulin signaling and fat accumulation induced by the dietary fatty acids and fructose. C57BL/6 type 8 week-old male mice (n = 10/per group) were fed with standard chow or three isocaloric diets consisting fructose, monounsaturated fatty acids (MUFA), or saturated fatty acid (SFA) for 15 weeks. After the dietary manipulation, the mice were sacrificed, tissues and blood were collected. Consequently, body weight gains, liver weights, and plasma homeostasis model of assessment-insulin resistance (HOMA-IR) values in were at higher levels in SFA and fructose groups (p < 0.05). The plasma concentrations of the non-esterified fatty acids (NEFA), triglyceride (TG), and liver steatosis were found to be at higher levels in SFA and fructose groups (p < 0.05). Moreover, the expression levels of acetyl-CoA carboxylase-1 (ACC1), insulin receptor substrate-1 (IRS1), AMP-activated protein kinase (AMPK), and toll-like receptor-4 (TLR4) in the liver were affected by the intake of SFA and fructose. Furthermore, the plasma levels of C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP1) and the thiobarbituric acid reactive substances (TSARS) in the liver were elevated in SFA and fructose group (p < 0.05). The plasma level of anti-inflammatory cytokine interleukin-10 (IL-10) was found to be lower in the SFA group compared to the other groups (p < 0.05). In conclusion, the inflammation and oxidation are related with the fatty acid- and fructose-induced impaired insulin signaling and fat accumulation in liver. Hence, in order to decrease the oxidative stress and pro-inflammatory response, it is substantial to reduce the saturated fat and added sugar or to replace with the unsaturated fat and complex carbohydrates in diet.