Background/Objectives: Orally disintegrating tablets (ODTs) are often used for patients with dysphagia; however, their co-administration with “thickened water” in clinical settings can delay disintegration and potentially reduce therapeutic efficacy. While wicking networks formed by superdisintegrants facilitate rapid disintegration, we hypothesized that viscous polymers in thickened water cause “pore clogging” within these networks. Although conventional macroscopic evaluations have demonstrated this delay, direct visualization of the underlying microstructural changes remains unexplored. Therefore, this study aimed to elucidate the microstructural mechanisms of disintegration delay. Methods: Simplified model ODTs containing either a wicking-type (crospovidone [CP]) or a swelling-type (sodium starch glycolate [SSG]) disintegrant were prepared. Their microstructures and disintegration behaviors were evaluated by cryogenic focused ion beam scanning electron microscopy (Cryo-FIB-SEM), three-dimensional (3D) X-ray computed tomography (CT), and disintegration tests under simulated gastric conditions (pH 1.2). Results: Cryo-FIB-SEM revealed that CP-containing tablets formed numerous channel-like pores that promoted capillary action upon contact with water, whereas SSG-containing tablets formed larger, isolated macropores. X-ray CT analysis demonstrated distinct low-density regions associated with penetration-induced structural changes in both formulations. In CP-containing tablets, these regions extended throughout the channel network, whereas in SSG-containing tablets they were largely confined to the tablet surface. Consequently, the disintegration of CP-containing tablets in simulated gastric fluid was significantly delayed compared to that of SSG-containing tablets. Conclusions: The findings are consistent with a pore-clogging mechanism in which penetration of a viscous medium interferes with the liquid transport pathways responsible for rapid tablet disintegration. Combined Cryo-FIB-SEM and X-ray CT imaging provided direct morphological evidence of disintegrant-dependent structural responses in viscous media and offers a new framework for mechanistic investigation of tablet disintegration processes.