Background: Statins are cholesterol lowering drugs that decrease the risk of cardiovascular events, but they are related with a few unfavorable symptoms in skeletal muscle including myopathy, and mild to moderate fatigue. Additionally, there has been discrepancies about the impacts of statins on brain and cognition. This study aimed to examine the impacts of two different statins, lipophilic simvastatin and hydrophilic rosuvastatin on cognitive functions in normal healthy rats. Simultaneously, we investigated the alterations of neurotropins and irisin levels in hippocampus and myokine levels in skeletal muscle. Methods: The rats were dosed with 88 mg kg body weight−1 day−1 simvastatin (n = 8), 150 mg kg body weight−1 day−1 rosuvastatin (n = 8) or vehicle (n = 8) for 18 days via oral gavage. After that behavioral assessment was performed and hippocampus and skeletal muscle samples were taken for the analysis of neurotrophins and irisin levels. Results: Locomotion and learning and memory functions were lower, but anxiety levels were higher in the simvastatin and rosuvastatin groups than in the control group (P < 0.05). Hippocampal neurotrophins and irisin levels were lower, but skeletal muscle brain-derived neurotrophic factor (BDNF) and irisin levels were higher in the simvastatin and rosuvastatin groups than in the control group (P < 0.05). Conclusion: These findings suggest that high dose simvastatin and rosuvastatin impair cognitive functions via decreasing BDNF, NGF and irisin levels in the hippocampus.