Cancer is among the most common causes of death worldwide, therefore reaching effective and nontoxic novel anticancer agents is one of the top urgencies for medicinal chemists. 3- Methyl-quinazolin-4(3H)-one derivatives have been extensively investigated for their potential as anticancer drug candidates. In the light of these considerations, we designed and synthesized some new 3-methyl-quinazolin-4(3H)-ones, and investigated their cytotoxic activities. 3- Methyl-quinazolin-4(3H)-one, which was prepared by the reaction of anthranilic acid with methyl isothiocyanate, was treated with proper 1-aryl-2-bromoethan-1-one and N-aryl-2- chloroacetamide derivatives in the presence of potassium carbonate to synthesize the title amides 7-19. The N-acylhydrazone derivatives 5-6 were obtained by condensation of a hydrazide compound with appropriate aldehydes in the presence of acetic acid. The structures of the target compounds were elucidated by IR, 1H-NMR, mass spectrometry and the 3-D structure of 9 was determined by single-crystal X-ray diffraction analysis. 9 crystallizes in orthorhombic system with space group Pna21. All compounds were submitted to the National Cancer Institute (NCI) for cytotoxicity screen and tested at 10 μM in the full NCI 60 cell panel. The activity data of the compounds are expressed as growth inhibition relative to the no-drug control and relative to the time zero number of cells. According to the results, four out of 15 compounds caused at least 50% growth inhibition against at least one cell line. Generally, the tested compounds were the most cytotoxic against breast and ovarian cancer cell lines (T-47D and OVCAR-4, respectively). 2-((2-(Furan-2-yl)-2-oxoethyl)thio)-3-methylquinazolin-4(3H)- one (18) was the most active compound with 94.1 and 81.7% growth inhibition against two breast cancer cell lines (MDA-MB-468 and MCF7, respectively). The cytotoxic activities of the compounds were screened under Developmental Therapeutics Program (DTP) by NCI, The Division of Cancer Treatment and Diagnosis (DCTD). Single crystal X-ray diffraction study was performed by Jan Moncol.