Naked mole rats (NMRs) are renowned for their exceptional longevity and remarkable maintenance of health throughout their lifetime. Their subterranean lifestyle has led to adaptations that have resulted in elevated levels of a very high molecular weight hyaluronan in their tissues. Hyaluronan, a glycosaminoglycan, is a key component of the extracellular matrix, which plays a critical role in maintaining tissue structure and regulating cell signaling pathways. This phenomenon in NMRs is attributed to a higher processing and production capacity by some of their hyaluronan synthases, along with lower degradation by certain hyaluronidases. Furthermore, this adaptation indirectly confers several advantages to NMRs, such as the preservation of skin elasticity and youthful appearance, accelerated wound healing, protection against oxidative stress, and resistance to conditions such as cancer and arthritis, largely attributable to CD44 signaling and other intricate mechanisms. Thus, the main objective of this study was to conduct a comprehensive study of the distinctive features of NMR hyaluronan, particularly emphasizing the currently known molecular mechanisms that contribute to its beneficial properties. Furthermore, this research delves into the potential applications of NMR hyaluronan in both cosmetic and therapeutic fields, as well as the challenges involved.