Natural polymers have attracted significant attention in drug delivery applications due to their biocompatibility, biodegradability, and versatility. However, their surface properties often limit their use as drug delivery vehicles, as they may exhibit poor wettability, weak adhesion, and inadequate drug loading and release. Plasma treatment is a promising surface modification technique that can overcome these limitations by introducing various functional groups onto the natural polymer surface, thus enhancing its physicochemical and biological properties. This review provides a critical overview of recent advances in the plasma modification of natural polymer-based drug delivery systems, with a focus on controllable plasma treatment techniques. The review covers the fundamental principles of plasma generation, process control, and characterization of plasma-treated natural polymer surfaces. It discusses the various applications of plasma-modified natural polymer-based drug delivery systems, including improved biocompatibility, controlled drug release, and targeted drug delivery. The challenges and emerging trends in the field of plasma modification of natural polymer-based drug delivery systems are also highlighted. The review concludes with a discussion of the potential of controllable plasma treatment as a versatile and effective tool for the surface functionalization of natural polymer-based drug delivery systems