Abstract: Background and Objective: Zygophyllum simplex is commonly used in Saudi Arabia for the treatment of horny patches of skin and as an anthelmintic, analgesic and anti-inflammatory. The experiment was to aimed at to evaluate the constituents of Zygophyllum simplex extract and their effect on blood biochemical parameters in Wistar male rats. Methodology: The plant extract was orally administered to the rats (n = 10) at two doses of 250 and 500 mg kg–1 b.wt., for 30 days. Its effects on glucose, total cholesterol, triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine kinase (CK), total protein, total bilirubin and blood urea were investigated. Results: The results showed a significant decrease in total serum cholesterol, blood glucose and CK levels. However, levels of AST, ALT, triglycerides, total bilirubin, total protein and blood urea were unaltered. Conclusion: In coclusion, the ethanolic extract of Z. simplex may act as hypoglycemic and hypolipidimic in rats.