Abstract Diabetes mellitus (DM) establishes a perilous synergy with periodontal disease, creating a bidirectional relationship that exacerbates both conditions. The foundation of this synergy lies in the metabolic dysregulation and immunoinflammatory paralysis induced by chronic hyperglycaemia, which precipitates a significant dysbiosis within the oral microbiome. This shift in microbial ecology, characterised by an enrichment of proteolytic, inflammatory pathobionts and a depletion of health-associated commensals, fuels a cycle of accelerated periodontal tissue destruction and impaired healing capacity. Conventional periodontal therapies often yield suboptimal outcomes in diabetic patients due to this compromised regenerative microenvironment. In this context, biologically active autologous materials like injectable Platelet-Rich Fibrin (i-PRF) have emerged as a promising therapeutic adjunct. i-PRF serves as a reservoir of growth factors and a natural, polymerisable scaffold that can directly counter the pathophysiological hurdles of the diabetic periodontium. This comprehensive review meticulously examines the complex interplay between diabetes and alterations in the oral microbiome, detailing how these shifts influence the progression of periodontal disease. Furthermore, it critically appraises the regenerative potential of i-PRF, synthesising clinical and histological evidence to propose a novel, integrative treatment paradigm that combines microbial modulation with advanced biomaterial-based regeneration to redefine periodontal management in the diabetic population.