The objective of the current study was to evaluate the toxicity of oral administration of three synthesized organic compounds by us; 2‐Amino‐3‐benzyl‐6‐(benzylthio) pyrimidin‐4(3H)‐one (amino pyrimidine), 3‐Benzyl‐7‐hydroxy‐5‐(4‐ hydroxyphenyl)‐2‐(phenylamino)pyrido [2,3‐d]pyrimidin‐4(3H)‐one (pyridopyrimidine) and N -{[1-Benzyl-4-(benzylthio)-6-oxo-1,6-dihydropyrimidin-2-yl]carbamothioyl}benzamide (pyrimidine benzamide) for 28 days on some biochemical parameters and hepatic and renal histopathological changes in male albino rats. All the three tested pyrimidine's derivatives showed significant decrease of the body weight, total proteins and significant increase in liver weight and liver index when compared to control group. Additionally, the activities of serum transaminases (ALT and AST) and alkaline phosphate (ALP) were increased significantly in amino pyrimidine, pyridopyrimidine and pyrimidine benzamide treated groups when compared to control group. Moreover, significant inhibition of serum cholinesterase activity (ChE) and hemoglobin (Hb) value were observed with oral administration of the three investigated pyrimidine's derivatives in comparison to control rats. Concerning renal function indicators; serum urea was increased significantly in rats after receiving amino pyrimidine, pyridopyrimidine and pyrimidine benzamide. On the other hand, creatinine levels were increased by administration of amino pyrimidine, pyridopyrimidine and pyrimidine benzamide.The MDA level was detected to be increased significantly and TAC was decreased significantly in rats received amino pyrimidine, pyridopyrimidine, and pyrimidine benzamide. Histopathological examination of rats administered amino pyrimidine, pyridopyrimidine and pyrimidine benzamide, revealed disturbed hepatic and renal architecture that confirm the biochemical results which report hepatic and renal damage. The obtained data demonstrate the toxic effect of the evaluated fused pyrimidine derivatives in male albino rats.