This study evaluated the pathogenicity of Acanthamoeba polyphaga in immunosuppressed mice, focusing on its histopathological effects on the kidneys and lungs. Fifty male Swiss albino mice were divided into three groups: immunosuppressed uninfected (CS), immunosuppressed Acanthamoeba polyphaga infected (AS), and negative controls (C). The CS and AS groups were sacrificed at 2, 7, and 15 days post-infection (dpi). Histopathological analysis of infected kidneys revealed inflammatory cell infiltration in the renal cortex including periglomerular, perivascular, and interstitial tissues, which was evident at 2 and 7 dpi. Additionally, necrosis in the tubular epithelium nuclei was observed more evident at 15 dpi and distribution of parasite stages in the periglomerular and perivascular areas. The parasite was successfully re-isolated from freshly dissected infected kidney tissues at 2 dpi. Physiological assessment indicated a significant increase in renal biomarkers (urea and creatinine) at 7 and 15 dpi. In the lungs, histopathological findings included perivascular inflammatory cell infiltration, thickening of alveolar septae (a pathognomonic lesion for pneumonia), and congestion in the blood vessels at 7 and 15 dpi. However, lung tissues showed negative results in the re-isolation test. These findings highlight the systemic pathogenic potential of A. polyphaga in immunosuppressed hosts, particularly its pronounced impact on histopathology and renal function and moreover, its presence and impact on lung tissues.