The synthesis, in vivo and in vitro antitumor evaluation, and QSAR studies of some novel pyrazole analogs against Ehrlich Ascites Carcinoma (EAC) cells were described. In vitro results revealed that compounds 10, 6 and 4 were the most potent analogs against EAC, respectively. Moreover, in vivo evaluation of compounds 6 and 10 proved their capability to normalize the blood picture in comparison to 5-FU, a well known anticancer drug. These novel pyrazole analogs were molecularly designed with the goal of having significant potent cytotoxic effect against EAC cells. To develop a QSAR model capable of identifying the key molecular descriptors associated with the biological activity of the novel pyrazole analogs and predicting the cytotoxic effect for other novel pyrazole analogs against EAC cells, different QSAR models, using different physicochemical and topological molecular descriptors, were developed. Different molecular descriptors were predicted solely from the chemical structures of 16 pyrazolo-diazine and triazine analogs following the prediction of the equilibrium molecular geometry of each analog at the DFT level using B88-LYP functional energy and double zeta valence polarized (DZVP) basis set. It was found that dipole moment, excitation energy, the energy value of LUMO, solvent accessible surface area, and heat of formation were the key molecular descriptors in descriping the cytotoxic effect of those compounds against EAC.