Precision medicine requires precise regulation of drugs in terms of time, space, and dosage. Exogenous control systems, such as electrical responsiveness, have made great progress. However, wearable or implantable controlled drug release devices still face major challenges due to limitations including limited battery life, large size, and fixed power supply. To overcome these limitations, the fabrication of autonomous devices is available to endure extended periods without reliance on external power sources. As a promising strategy, nanogenerators (NGs) turn body mechanical energy into electricity, powering long-term drug release. In this review, the current status of drug delivery systems (DDS) is briefly outlined and the importance of self-driven controlled drug release systems is emphasized. The main types and operational mechanisms of various nanogenerators are introduced. This review also focuses on summarizing the latest progress of self-powered controlled drug release systems based on nanogenerators (NG-based CDRs). Additionally, their applications in the field of drug release are introduced in detail. Finally, the existing challenges and future trends of self-powered NG-based CDRs are discussed from the perspectives of clinical needs and practical translation.