Maintenance of homeostasis is the primary function of the immune system. It detects the threats posed by pathogens, cancer, and tissue damage and mounts an immune response. The immunological memory dispensed by the immune system prevents or minimizes a second attack by the pathogen. Owing to the advent of new technologies, the comprehension of the immune system has widened, thus opening new horizons to modulate the immune system against any threat. Modulating the immune system with several biological and synthetic molecules mainly targets the innate and adaptive immune system to mount responses against several types of cancers, pathogenic infections, and autoimmune diseases. Polymers are widely used in several biological applications. The various characteristics of polymers, including molecular weight and tunable properties to modulate certain biological functions, have rendered them an ideal candidate for developing state-of-the-art therapeutic interventions. Extensive studies by various researchers across the globe have unraveled the potential of several synthetic and natural polymers to exhibit immunostimulatory activities. These polymers act as pattern recognition receptors (PRR) agonists to activate and engage the immune system. Despite polymeric nanoformulations and scaffolds being used to ferry molecular cargo, targeted delivery to specific cells, and interact with biological molecules, the innate potential of the polymers to influence the immune system is still little understood. From this perspective, this review discusses the very commonly used natural polysaccharides, which are also polymers, and their innate immunomodulatory potentials, mostly focusing on the molecular pathways influenced by the polysaccharides in the immunomodulation process. Further, the challenges associated with the application of polysaccharides and the potential solutions have also been discussed. © 2023 Elsevier Ltd