Three new cobalt(II) complexes, [Co(MQL)2Cl2] (CoCl), [Co(MQL)2Br2] (CoBr), and [Co(MQL)2I2] (CoI), bearing 8-methoxyquinoline (MQL) have been designed for the first time. MTT assays showed that CoCl, CoBr, and CoI exhibit much better antiproliferative activities than cisplatin toward cisplatin-resistant SK-OV-3/DDP and SK-OV-3 ovarian cancer cells, with IC50 values of as low as 0.32-5.49 μM. Further, CoCl and CoI can regulate autophagy-related proteins in SK-OV-3/DDP cells and, therefore, they can induce primarily autophagy-mediated cell apoptosis in the following order: CoCl > CoI. The different antiproliferative activities of the MQL complexes CoCl, CoBr, and CoI could be correlated with the lengths of their Co-X bonds, which adopted the following order: CoI > CoBr > CoCl. The 8-HOMQ complexes CoCl (ca. 60.1%) and CoI (ca. 48.8%) also showed potent in vivo anticancer effects after 15 days of treatment. In summary, the MQL ligand highly enhances the antiproliferative activities of cobalt(II) complexes in comparison to other previously reported 8-hydroxyquinoline metal complexes.