Chronic Liver Disease (CLD) represents a progressive and irreversible spectrum of hepatic disorders characterized by sustained injury to hepatocytes and gradual architectural distortion of the liver parenchyma, ultimately culminating in fibrosis, cirrhosis, and hepatic insufficiency. The liver’s unique microanatomy-comprising hepatocytes arranged in plates, hepatic sinusoids, portal tracts, bile canaliculi, and the space of Disse-undergoes sequential structural remodeling during the course of chronic liver injury. Early alterations predominantly involve functional and ultrastructural changes within hepatocytes, including cellular swelling, steatosis, mitochondrial dysfunction, and endoplasmic reticulum stress, while advanced stages are marked by hepatocyte loss, regenerative nodules, fibrous septa formation, and distortion of lobular architecture. Understanding the applied anatomy of hepatocytes and their relationship with sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells is essential for correlating structural damage with clinical manifestations, biochemical abnormalities, and radiological findings in CLD. This review analyzes the applied hepatic anatomy with emphasis on hepatocyte-centered structural changes observed in chronic liver disease, integrating evidence from histopathology, imaging studies, and contemporary hepatology literature. Structural alterations at the cellular and lobular levels are correlated with functional consequences such as impaired protein synthesis, cholestasis, portal hypertension, coagulopathy, metabolic dysregulation, and hepatic encephalopathy. Radiological features including altered liver echotexture, surface nodularity, segmental hypertrophy–atrophy, and features of portal hypertension reflect underlying hepatocellular injury and progressive architectural remodeling. An integrated understanding of hepatocyte anatomy, histology, and imaging provides a comprehensive framework for early diagnosis, disease staging, prognostication, and effective management of Chronic Liver Disease.