Multidrug resistance to chemotherapeutic drugs is one of the major causes for the failure of cancer treatment. Therefore, there is an urgent need to develop anticancer agents that can combat multidrug-resistant cancers effectively and mitigate drug resistance. Here, we report a rational design of anticancer heterochiral β-peptide polymers as synthetic mimics of host defense peptides to combat multidrug-resistant cancers. The optimal polymer shows potent and broad-spectrum anticancer activities against multidrug-resistant cancer cells and is insusceptible to anticancer drug resistance owing to its membrane-damaging mechanism. The in vivo study indicates that the optimal polymer efficiently inhibits the growth and distant transfer of solid tumors and the metastasis and seeding of circulating tumor cells. Moreover, the polymer shows excellent biocompatibility during anticancer treatment on animals. In addition, the β-peptide polymers address those prominent shortcomings of anticancer peptides and have superior stability against proteolysis, easy synthesis in large scale, and low cost. Collectively, the structural diversity and superior anticancer performance of β-peptide polymers imply an effective strategy in designing and finding anticancer agents to combat multidrug-resistant cancers effectively while mitigating drug resistance.