Background: Neonicotinoids have become the most widely used class of insecticides with a global market share of more than 25%. They are a class of neuroactive insecticides chemically related to nicotine. Thiamethoxam is a second generation neonicotinoid insecticide in the thianicotinyl subclass used worldwide that contains nitro group. Acetamiprid is a systemic insecticide, belonging to the chloronicotine subclass and having a broad insecticidal spectrum that contains cyano group. Aim: The present study aims to investigate: Toxic effects of some neonicotinoid insecticides (Thiamethoxam and Acetamiprid) and investigate also biochemical, hematological and histological alterations of these insecticides. Materials & Methods: Adult male Swiss albino rats were divided into 3 groups: 1st negative control group; 2nd Thiamethoxam group administrated 156 mg/Kg body weight every day along 30 days; 3rd Acetamiprid group administrated orally 100 mg/Kg body weight every day along 30 days. Blood, liver and kidney tissues samples were collected for some biochemical, hematological and histopathological studies. At the end of the experiment, animals were scarified every 10, 20 and 30 days. Results: Thiamethoxam and Acetamiprid induced alterations in liver function tests, kidney function tests and hematological parameters. As these changes were accompanied with hepatic necrosis as well as inflammation. Moreover, they induced cloudy swelling of renal tubules and renal inflammation. Conclusion: Our data suggested that, Thiamethoxam may be more hepatotoxic, nephrotoxic and produced hematological changes than Acetamiprid. Use of these insecticides should be limited.