Nanoparticles (NPs) are being used in several industries worldwide and can introduce into the human body through different exposure routes, including inhalation, oral administration, intravenous injection, and intramuscular or transdermal delivery. The present in vivo study aimed to evaluate the acute oral toxicological effects of silica (SiO2) and magnesium oxide (MgO) NPs in rats by using histological, biochemical, and biodistribution parameters. The results revealed that acute exposure to higher doses of these NPs produced a significant decrease (p < 0.05) in alanine aminotransferase, alkaline phosphatase serum levels lactate dehydrogenase, and aspartate aminotransferase. Mild congestion, non-zonal hepatocellular swelling and degeneration, and apoptotic cells with significant pyknotic or shrunken nuclei were found in the liver of the treated rats at 2000 mg/kg of the MgO NPs. Moreover, under the microscopic examination, focal hepatocellular degeneration and necrosis, accumulation of mononuclear inflammatory cells within the necrotic area and in the portal tract, and severe central vein and sinusoidal congestion and focal edematous fluids in the hepatic parenchyma were observed in the livers of the treated rats with 2000 mg/kg of SiO2 NPs. Moreover, MgO NPs exhibited higher liver and kidney accumulation than SiO2 NPs. In conclusion, these NPs at a high concentration could have toxicological effects on rats' liver and kidney tissues. However, further studies require examining the safety and the other possible toxic effects of these NPs before entering the consumer market.