The generation and delivery techniques of cold atmospheric plasma (CAP), coupled with their innovative applications in treating various diseases, have given rise to plasma medicine as a novel therapeutic modality, offering new approaches for managing chronic diseases. CAP therapy generates a large number of reactive species that selectively modulate biological activities, yielding long-lasting effects and minimizing the risk of drug resistance, which is challenging to achieve with small molecule drugs. However, before CAP can be effectively utilized in chronic disease treatment, numerous limitations must be addressed. This review comprehensively summarizes the latest research progress in CAP-based chronic disease treatments, with a focus on the main CAP generation devices, delivery methods, and therapeutic mechanisms. Additionally, it addresses the key scientific issues in the development of plasma medicine, aiming to optimize therapeutic outcomes and provide a robust theoretical foundation and guiding principles for the effective clinical implementation of CAP.