Giardiasis is the major water-borne diarrheal disease present worldwide caused by the common intestinal parasite, Giardia duodenalis. This work aims to investigate the effect of G. duodenalis infection pathogenicity in immunosuppressed animals through histopathological examination. A total of 45 BALB/c mice were divided into four groups; G1 (negative control), G2 (healthy animals exposed to Giardia); G3 (immunosuppressed animals exposed to Giardia), and G4 (non-exposed immunosuppressed animals). Our study revealed that G3 was the most affected group with an infection rate of 100%. The animals showed general weakness, soft stool, and high death rate with severe histopathological changes in the duodenum and mild degenerative changes in hepatic tissues. In G2, the maximal lesions in both duodenum and liver were on the 11th day. We spotted damage in the villi, edema in the central core, and submucosa, in addition to increased cellular infiltration with inflammation in lamina propria. The presence of the parasites within the villi and the lumen was clear. Most of the hepatocytes revealed hydropic and fatty changes, also dilated congested central veins and edema were observed. G3 changes were more intense than G2 with massive Giardia trophozoites between the intestinal villi, lumen, and extensive fatty liver degeneration. Immune suppression plays a significant role in the severity of injury with the Giardia parasites in duodenum and liver cells.