Hyaluronan (HA) is a naturally occurring non-sulfated glycosaminoglycan (GAG), cell-surface-associated biopolymer and is the key component of tissue extracellular matrix (ECM). Along with remarkable physicochemical properties, HA also has multifaceted biological effects that include but not limited to ECM organization, immunomodulation, and various cellular processes. Environmental cues such as tissue injury, infection or cancer change downstream signaling functionalities of HA. Unlike native HA, the fragments of HA have diversified effects on inflammation, cancer, fibrosis, angiogenesis and autoimmune response. In this review, we aim to discuss HA as a therapeutic delivery system development process, source, biophysical-chemical properties, and associated biological pathways (especially via cell surface receptors) of native and fragmented HA. We also tried to address an overview of the potential role of HA (native HA vs fragments) in the modulation of inflammation, immune response and various cancer targeting delivery applications. This review will also highlight the HA based therapeutic systems, medical devices and future perspectives of various biomedical applications were discussed in detail.