Inflammation is a physiological response of the body to infection and tissue damage; dysregulated inflammatory signaling can cause the initiation and aggravation of a variety of chronic diseases. Although anti-inflammatory drugs have been commercialized and showed beneficial effects clinically, their long-term application is often limited by loss of effects and adverse side effects. Natural polysaccharides are multifunctional biomacromolecules with strong potentials in inflammation therapy due to their inherent biocompatibility, wide immunomodulation property and drug capacity. In this Review, we offer a holistic summary of recent advances in polysaccharide anti-inflammatory strategies by coupling the characteristics of structure, biological mechanism and polysaccharide-based delivery systems. This review gives a comprehensive overview of the rational design of anti-inflammatory strategies based on polysaccharides, and also points out the current limitations of polysaccharide drugs in applications, translation difficulties and future trends.