Over the past few decades, traditional drug delivery systems have been extensively investigated and applied in clinical settings. However, they still face several limitations, including low delivery efficiency, short circulation times in vivo, and potential toxicity. In contrast, red blood cell (RBC)-based drug delivery systems have attracted considerable attention owing to their excellent biocompatibility, prolonged circulation half-life, immune evasion capability, low cytotoxicity, and low tissue toxicity. Therefore, the development of RBC-based drug delivery systems is a promising strategy for improving therapeutic efficacy and advancing the treatment of refractory diseases. Currently, the major construction strategies for RBC-based drug delivery systems include intracellular loading approaches, surface engineering and loading strategies, and RBC membrane-based biomimetic carrier construction. These approaches have demonstrated substantial potential for enhancing drug stability, prolonging systemic circulation time, and improving the efficiency of targeted delivery. Nevertheless, most RBC-based drug delivery systems remain at the preclinical stage, and several critical challenges—including large-scale manufacturing, clinical translation, precise control of drug release kinetics, and long-term biosafety evaluation—must be overcome before their clinical applicability and therapeutic potential can be fully realized.