Helicobacter pylori stands as a preeminent human-specific pathogen and the primary causative agent of chronic gastritis, peptic ulcer disease, and gastric adenocarcinoma. Central to its pathogenicity is the capacity to establish persistent colonization within the harsh acidic milieu of the stomach, a process in which bacterial adhesion to the gastric epithelium represents the indispensable initiating step. The first line of defense against microbial intrusion is mounted by gastric mucosal mucins and their elaborate O-glycosylation modifications, which together constitute both a physicochemical barrier and an immunomodulatory interface. The gel-forming mucins MUC5AC and MUC6, secreted by surface foveolar and glandular epithelial cells respectively, together with the membrane-tethered MUC1, are heavily decorated with structurally diverse O-glycans. The proper presentation of terminal glycan determinants—including Lewis b (Le^b), sialyl-Lewis x/a (sLe^x/sLe^a), and ABO histo-blood group antigens—is fundamental to maintaining mucosal integrity and resisting pathogen invasion. However, Helicobacter pylori infection profoundly disrupts this equilibrium by altering the expression levels and glycosylation patterns of host gastric epithelial mucins, thereby reshaping the very landscape it seeks to exploit. This review synthesizes current understanding of how Helicobacter pylori orchestrates mucosal colonization through a multivalent glycan-adhesin recognition system. The bacterium deploys an array of outer-membrane adhesins—most notably BabA and SabA—to specifically engage host gastric mucosal receptors, including Le^b, sialylated glycans, and related structures. By binding these carbohydrate ligands, Helicobacter pylori anchors itself firmly within the mucus layer and along the epithelial surface, effectively converting host defensive glycans into molecular footholds that facilitate initial attachment and long-term persistence. We posit that this glycan-adhesin crosstalk constitutes not only the gateway to initial colonization but a sustained pathogenic axis that actively perpetuates chronic inflammation and co-opts host glycosylation pathways throughout the infection course. These glycan-adhesin interactions not only determine bacterial tropism and colonization efficiency but also enable Helicobacter pylori to adapt to dynamic changes within the gastric microenvironment. Beyond this adhesive strategy, Helicobacter pylori infection provokes extensive mucosal and bacterial responses on two parallel fronts. On the host side, Helicobacter pylori-derived products and epithelia-derived chemokines drive robust neutrophil recruitment, which amplifies the local inflammatory response. On the bacterial side, under diverse environmental stresses encountered during chronic colonization—including, among others, nutrient deprivation, aerobic exposure, sublethal antibiotic pressure, proton-pump inhibitor intervention, and altered intragastric pH—the spiral bacilli undergo profound intracellular remodeling and progressively transition into dense coccoid forms, enabling the pathogen to transit into viable-but-non-culturable (VBNC) coccoid forms that exhibit enhanced resilience and tolerance to environmental stressors. Furthermore, lipopolysaccharide (LPS), an essential component of the Helicobacter pylori outer membrane, undergoes extensive glycosylation modifications that allow the bacterium to mimic host Lewis blood group antigens. This glycan camouflage serves a dual pathological role. On one front, it enables the bacterium to evade innate immune detection, thereby sustaining chronic persistent infection. On another, the presentation of host-like antigenic determinants provokes the production of cross-reactive autoantibodies, which mistakenly target autologous gastric epithelial components and exacerbate mucosal inflammatory injury. These interconnected mechanisms—adhesin-mediated colonization, inflammation-driven bacterial adaptation, and LPS-mediated immune subversion—act in concert to drive the progressive amplification of gastric mucosal inflammation and the stepwise evolution of precancerous lesions along the Correa cascade. Despite advances in understanding Helicobacter pylori pathogenesis, current clinical management remains encumbered by significant limitations. Conventional antibiotic-based eradication regimens are increasingly compromised by rising global rates of bacterial resistance to key drugs such as clarithromycin and metronidazole, the intrinsic difficulty of eradicating VBNC spherical forms, and persistently high post-treatment recurrence rates in endemic settings. In this context, anti-adhesion therapy targeting glycan-adhesin interactions has emerged as a promising alternative strategy. By competitively blocking bacterial attachment rather than directly killing bacteria, glycan-based inhibitors may reduce selective pressure for resistance development and provide a novel approach for controlling persistent infections. We therefore propose that anti-adhesion therapy should be reconceptualized as a longitudinal intervention targeting the entire colonization-persistence-progression continuum, rather than merely an adjunct to conventional eradication. However, several challenges remain before glycan-targeted therapies can be translated into clinical practice. The structural complexity and heterogeneity of host glycans, individual variations in gastric glycosylation patterns, and the difficulty in achieving highly specific targeting represent major obstacles. Future research integrating glycomics, microbiome analysis, structural biology, artificial intelligence-based prediction models, and precision medicine approaches may facilitate the identification of optimized glycan mimetics and personalized anti-adhesion therapies. Such advances will promote the transition of glycan-based intervention strategies from mechanistic exploration toward practical clinical applications, offering new opportunities for the prevention and treatment of Helicobacter pylori-associated gastric diseases.