The global pandemic of drug-sensitive cancers and the increasing threat from drug-resistant cancers make an urgent need to develop more effective anti-cancer candidates. Quinolone derivatives possess promising anti-cancer activity, and some of them have already been approved to treat cancers or under clinical trials. Hybridization of quinolone with other anti-cancer pharmacophores may provide more efficient anti-cancer candidates, so quinolone hybrids worth to be investigated. In this review, the recent advances in the development of novel quinolone hybrids as potential anti-cancer agents are highlighted, and the structure-activity relationship is also discussed to provide an insight for further development of more active quinolone hybrids.