This study was carried out to evaluate and compare the possible toxic effect among some synthetic and natural food colorants on biochemical parameters as well as liver and kidney histological of experimental rats. A total number of 45 young albino male rats (weight about 100-120 g) were used in this study. All rats were divided randomly into nine groups and fed on tested diets for four weeks (carmoisine, raspberry, sunset-yellow, and fast green as synthetic colorants; and anthocyanin, betalain, carotenoids, and chlorophyll as natural food colorants; as well as a control group). The results showed a significant increase in levels of serum alanine aminotransferase, aspartate aminotransferase, urea, creatinine, total protein, and albumin, with decreased levels of immune-globulins were observed in all groups treated by synthetic colorants groups compared to the groups treated by natural food colorants and control group. Histological examinations revealed alterations in kidneys including congestion and hemorrhage with infiltration, and deformation of the glomeruli structure. Whereas, alterations in the liver including congestion, hemorrhage, and dilatation of sinusoids and central vein with microvascular steatosis. Therefore, it is advisable to limit the uses of synthetic food colorants or replacing them with natural ones, especially for children's foods.