Hyaluronan (HA) is a linear polysaccharide consisting of disaccharide units which are the D-glucuronic acid and N-acetyl-D-glucosamine. As the largest component of the extracellular matrix in microenvironment, HA polymers with different molecular weights vary in properties to molecular biology function. High molecular weight HA (HMW-HA) is mainly found in normal tissue or physiological condition, and exhibits lubrication and protection properties due to its good water retention and viscoelasticity. On the other hand, an increase in HA catabolism leads to the accumulation of low molecular weight HA (LMW-HA) under pathological circumstances such as inflammation, pre-cancerous and tumor microenvironment. LMW-HA acts as extracellular signals to enhance tumorigenic and metastatic phenotype, such as energy reprogramming, angiogenesis and extracellular matrix (ECM) remodeling. This review discusses the basic properties of this simplest carbohydrate molecule in ECM with enormous potential, and its regulatory role between tumorigenesis and microenvironmental homeostasis. The extensive discoveries of the mechanisms underlying the roles of HA in various physiological and pathological processes would provide more information for future research in the fields of biomimetic materials, pharmaceutical and clinical applications.