Two platinum(II) complexes, [PtCl(Q)(DMSO)] (1) and [PtCl(IQ)(DMSO)] (2), bearing 8-hydroxyquinoline (H-Q) and 5,7-diiodo-8-hydroxyquinoline (H-IQ) as the bioactive ligand, respectively, were synthesized and structurally characterized. By MTT assay, complex 2 bearing the IQ ligand showed significantly higher growth inhibition than complex 1 against all the five typical tumor cell lines in the test, but showed no more cytotoxicity against the normal liver cell line HL-7702, suggesting the much better cytotoxic selectivity of 2 than that of 1. In addition, the HepG2 cell line was found to be the most sensitive towards both complexes. Aiming at the HepG2 cell line, both complexes arrested the cell cycle of HepG2 cells in the S phase, as examined by flow cytometry, in which complex 2 showed higher S-phase arrest than 1. This was supported by the down-regulation of cdc25 A, cyclin B, cyclin A, and CDK2 and the up-regulation of p53, p27 and p21 based on western blot assay. Complex 2 also acted as a more effective telomerase inhibitor than 1 by interacting with telomeric/c-myc G-quadruplexes and triggering cell senescence and cell apoptosis. Furthermore, both complexes caused mitochondrial dysfunction, suggesting a potential mitochondrion-mediated apoptotic pathway induced by each complex. From the platinum uptake assay, complex 2 exhibited obvious priority on the cell uptake effect than 1, which should be undoubtedly correlated with the key roles of the 5- and 7-iodo-substituted groups in the IQ ligand of 2. This may well explain the better cytotoxicity and the more significant antitumor mechanism of 2 throughout the study. This work further demonstrated that rational halogen substitution on selected ligands would be greatly beneficial to achieve more promising metal-based antitumor agents.