The present study aimed to synthesize new metal complexes of diacetylmonoxime-N(4)antipyrinylthiosemicarbazone ligand and evaluate their antitumor activity. New complexes with ferric, cobalt, nickel and copper ions were prepared. Elemental, ¹H Nuclear magnetic resonance, Mass spectroscopy, Electron paramagnetic resonance, Fourier Transform Infrared Spectroscopy, Ultraviolet–visible and thermal gravimetric analysis were used to characterize the obtained complexes 1–11. An in vivo tumor model was established to investigate the effect of the naked ligand and its metal complexes 2, 5 and 8. Ehrlich ascites carcinoma solid tumor was induced in mice through subcutaneous inoculation of Ehrlich ascites carcinoma cells. The volumes of the formed solid tumors, the alanine transaminase, aspartate transaminase, albumin concentration in the serum, as well as the levels of Ki67 and p53 proteins in tumor and liver tissues were detected. All the tested complexes, especially complex 5, possessed proliferative inhibition manifested as the reduction of the tumor volume, Alanine aminotransferase & Aspartate aminotransferase activity, and the level of the Ki67 protein. Additionally, they restored the albumin concentration to normal levels as well increased the level of pro-apoptotic p53 protein. In conclusion, the antitumor activity of the newly synthesized metal complexes against Ehrlich ascites carcinoma solid tumors was proved to be mediated by the inhibition of Ki67 and induction of p53 proteins.