Multidrug resistance (MDR) promotes tumor recurrence and metastasis and heavily reduces anticancer efficiency, which has become a primary reason for the failure of clinical chemotherapy. The mechanisms of MDR are so complex that conventional chemotherapy usually fails to achieve an ideal therapeutic effect and even accelerates the occurrence of MDR. In contrast, the combination of chemotherapy with dual-drug has significant advantages in tumor therapy. A novel dual-drug codelivery nanosystem, which combines dual-drug administration with nanotechnology, can overcome the application limitation of free drugs. Both the characteristics of nanoparticles and the synergistic effect of dual drugs contribute to circumventing various drug-resistant mechanisms in tumor cells. Therefore, developing dual-drug codelivery nanosystems with different multidrug-resistant mechanisms has an important reference value for reversing MDR and enhancing the clinical antitumor effect. In this review, the advantages, principles, and common codelivery nanocarriers in the application of dual-drug codelivery systems are summarized. The molecular mechanisms of MDR and the dual-drug codelivery nanosystems designed based on different mechanisms are mainly introduced. Meanwhile, the development prospects and challenges of codelivery nanosystems are also discussed, which provide guidelines to exploit optimized combined chemotherapy strategies in the future.