Amoebiasis, caused by Entamoeba histolytica, is a prevalent cause of dysentery in Southeast Asia. Conventional diagnosis heavily relies on non-invasive modalities like stool microscopy and serology; however, these diagnostic modality frequently suffer from low sensitivity and are confounded by regional endemicity. We present a rare case of invasive extraintestinal amoebiasis in a 78-year-old immunocompromised male with a history of diffuse large B-cell lymphoma. The patient presented with a three-week history of severe watery diarrhea, fever, and significant weight loss, ending in hypovolemic shock. Serial stool wet mount examinations were repeatedly negative for parasites, and Clostridioides difficile testing was negative. Due to his immunosuppressed status, a diagnostic colonoscopy was performed, revealing diffuse mucosal inflammation and severe sigmoid ulcerations. Histopathological examination of targeted colonic biopsies provided the definitive diagnosis, revealing numerous tissueinvasive trophozoites exhibiting erythrophagocytosis, which was further enhanced via Periodic acid- Schiff staining. The patient was successfully initiated on oral metronidazole. On day 22 of admission, hepatobiliary ultrasound screening revealed a concurrent 11 cm amoebic liver abscess, which required ultrasound-guided percutaneous drainage. Systemic exposure was retrospectively validated by a strong positive amoebic IgG serology. Following a sequential course of luminal eradication with paromomycin and targeted antibiotics, the patient achieved complete clinical recovery and was discharged well. This case highlights that when conventional non-invasive screening tools fail, an unconventional, multi-modal diagnostic approach utilizing early histopathology and proactive imaging is essential to optimize survival outcomes in complex, immunocompromised hosts.