α,β-Unsaturated chalcone moieties and quinoline scaffolds play an important role in medicinal chemistry, especially in the identification and development of potential anticancer agents. The multi-target approach or hybridization is considered as a promising strategy in drug design and discovery. Hybridization may improve the affinity and potency while simultaneously decreasing the resistance and/or side effects. The conjugation of quinolines with chalcones has been a promising approach to the identification of potential anticancer agents. Most of these hybrids showed anticancer activities through the inhibition of tubulin polymerization, different kinases, topoisomerases, or by affecting DNA cleavage activity. Accordingly, this class of compounds can be classified based on their molecular modes of action. In this article, the quinolone–chalcone hybrids with potential anticancer activity have been reviewed. This class of compounds might be helpful for the design, discovery and development of new and potential multi-target anticancer agents or drugs.