Konjac glucomannan (KGM) is a plant-derived polysaccharide with a long history of food use and a rapidly expanding portfolio of biomedical applications. Yet despite decades of research, translation of KGM-based materials from laboratory proof-of-concept to clinical and commercial products remains slow, hampered by unresolved structural controversies, batch-to-batch variability, and a lack of quantitative design rules. This review provides a critical, mechanism-focused analysis of KGM across its molecular architecture, extraction and modification, and translational applications, moving beyond cataloguing uses to evaluate conflicting findings in the literature. We examine how hierarchical structural features—molecular weight, acetylation pattern, and chain topology—govern solution behavior, gelation, and biological performance, and compare KGM with competing biopolymers to define its unique advantages and inherent limitations. Current progress in colon-targeted delivery, wound healing, microbiome modulation, and metabolic health is synthesized, and persistent barriers to translation are evaluated, including the absence of quantitative structure–activity models, limited human pharmacokinetic data, and incomplete toxicological characterization of modified derivatives. We also address longstanding debates over branching frequency, acetylation distribution, and dose–response relationships that have generated inconsistent results across studies. Finally, we outline a research agenda integrating computational polymer design, multi-omics mechanistic studies, and precision nutrition to support development of next-generation KGM biomaterials.