To develop the next-generation metal agents for efficiently inhibiting tumor growth, we synthesized a series of new Zn(II) complexes (C1-C5) derived from 2-pyridinecarboxaldehyde thiosemicarbazone and investigated their structure-activity relationships. C5 bearing two methyl groups at the N-4 position of the ligand exerted the strongest inhibition effect among all the Zn(II) complexes. Importantly, C5 exerted an effective inhibitory effect on tumor growth and produced few side effects in vivo. We further confirmed the antitumor mechanisms of C5, including arresting the cell cycle at the S phase, inducing apoptosis, inducing lethal autophagy, and suppressing angiogenesis.