Background: One of the serious public health problems in the world is metabolic syndrome. It includes visceral obesity, dyslipidemia, insulin resistance, hyperglycemia, and hypertension. As a contributor to almost all the classic signs of metabolic syndrome, fructose was the ideal choice. There are certain shortcomings with existing drugs for insulin-resistant treatment. Plants still represent the main source of most available medicines. Cinnamaldehyde (CNA) is an active principle of Cinnamomum zeylanicum. Costunolide (CE) is natural sesquiterpene lactones, which is the main bioactive constituent of Saussurea lappa. The main aim of the present study is to investigate the effect of the synthetic antidiabetic agent (metformin) in comparison with natural constituents (cinnamaldehyde, costunolide) after developing a reliable model for insulin resistance by using high fructose diet (HFD). Results: It was found that HFD increased plasma glucose, insulin, glycosylated hemoglobin, HbA1c, serum total cholesterol, LDL-cholesterol, triglyceride, ALT, AST, creatinine, and uric acid. Moreover, HFD decreased hepatic reduced glutathione and superoxide dismutase levels. While oral administration of cinnamaldehyde and costunolide significantly decreased plasma glucose, HbA1c, total cholesterol, LDL-cholesterol, triglyceride, and increased level of hepatic reduced glutathione and superoxide dismutase activity. Also, cinnamaldehyde and costunolide restored the altered plasma levels of ALT, AST, creatinine, and uric acid to normal. Conclusions: The results of this experimental study showed that cinnamaldehyde and costunolide could be used as safe drugs for treating different abnormalities of metabolic syndrome.