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Background: Management of giant pyogenic liver abscesses (PLA) remains challenging, particularly in culture-negative cases, where clinical improvement may not reflect adequate local disease control. Case Description: A 65-year-old woman with well-controlled type 2 diabetes mellitus presented with several weeks of systemic symptoms, marked inflammatory response, cholestatic liver injury, and acute kidney dysfunction. Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) revealed a large, multiloculated hepatic lesion measuring approximately 10 cm, consistent with a giant PLA. Empirical broad-spectrum antimicrobial therapy resulted in rapid clinical and biochemical improvement; however, follow-up imaging demonstrated further enlargement of the abscess. Microbiological cultures from blood, urine, and the abscess cavity remained negative. In view of radiological progression, CT-guided percutaneous catheter drainage was performed, resulting in effective evacuation and subsequent lesion regression. Long-term follow-up confirmed complete resolution without recurrence. Conclusions: This case highlights that clinical and laboratory improvement alone may be insufficient to assess treatment response in giant, culture-negative PLA. Serial imaging plays a key role in identifying inadequate local disease control and guiding timely escalation to image-guided intervention.