Intra-articular hyaluronan injections represent a widely used and generally safe therapeutic approach for knee osteoarthritis (OA). However, the side effects of this treatment remain insufficiently studied. Acute post-injection reactions, particularly those arising from an improper technique resulting in the deposition of the therapeutic agent into joint tissues, are well-documented. In contrast, chronic hyaluronan-induced inflammatory responses have received scant attention in the scientific literature. The aim of this study is to characterize for the first time the morphological patterns of chronic granulomatous inflammation induced by exogenous hyaluronan (e-HA) in osteoarthritic knees, focusing on three distinct tissue reactions: synovitis, adipositis, and osteomyelitis. Using a three-case series approach and morphological analysis, we identified e-HA penetration pathways; described associated foreign body responses in the synovial, adipose, and bone tissues of the joints; and emphasized the clinical relevance of these underreported adverse effects. These observations highlight an understudied phenomenon—an active conflict between e-HA and joint tissues that recognize it as a foreign body. The prevalence, clinical significance, and prognostic implications of this phenomenon require further investigation.