Hyaluronic acid is a natural glycosaminoglycan that is the main structural component of the extracellular matrix with unique physical and chemical properties that make it widely used in biomedical applications. The review summarizes current evidence that highlights the role of hyaluronic acid as an active signaling molecule modulating immune responses. The key factor in this response is the molecular weight of the polymer. High-molecular-weight fragments, which predominate in healthy tissues, when interacting with the CD44 receptor, suppress inflammation, promote the polarization of macrophages into an anti-inflammatory phenotype, enhance the suppressive function of regulatory T-lymphocytes, and support immune tolerance. Low-molecular-weight fragments, which are produced during trauma, ischemia, or oxidative stress, act as endogenous danger signals. They are recognized by TLR2 and TLR4 toll-like receptors, activate nuclear factor kappa B, and trigger a pro-inflammatory cascade with cytokine production. In contrast, ultra-short oligosaccharides can exhibit anti-inflammatory properties. The review provides a detailed analysis of hyaluronic acid receptors, mechanisms of its biosynthesis and degradation, as well as its cell-specific effects on macrophages, neutrophils, NK cells, T and B lymphocytes, dendritic cells, and stromal cells. Understanding the dual effects of hyaluronic acid opens new opportunities for therapeutic strategies in inflammatory, autoimmune, and cancerous diseases.