We developed a polymer–drug strategy to explore anticancer polymers. A series of monomers containing groups with potential anticancer activity have been facilely prepared through the Biginelli reaction. These monomers were used to produce water-soluble polymers through convenient radical copolymerization. The resulting polymers are biocompatible and can be directly used to suppress proliferation of different cancer cells without the release of small molecules. Theoretical calculations revealed that Biginelli groups in polymers had strong interaction with the Eg5 protein, which is highly expressed in cancer cells and is closely related to cell mitosis. Subsequent cell experiments confirmed that a screened polymer is efficient in inhibiting mitosis in different cancer cells. Our study of exploring functional polymers via the combination of multicomponent reactions and theoretical calculation resulted in promising anticancer polymers, which might pave a path for de novo designing of functional polymers and have important implications in the fields of organic, computational, and polymer chemistry.