Aim and background: Drug-induced liver injury (DILI) is a complex clinical challenge due to its varied presentations and the broad spectrum of potential causative agents. Early recognition and timely intervention are critical to prevent life-threatening complications. This report discusses a case of DILI caused by fluconazole and metolazone, complicated by hepatic encephalopathy and acute kidney injury (AKI) and highlights successful management strategies. Case description: Here, we are discussing a case of a 64-year-old male with a history of type 2 diabetes, hypertension, dyslipidemia, and benign prostatic hypertrophy. He presented with fever, loose stools, and altered sensorium. He had jaundice, dehydration, and a Glasgow Coma Scale (GCS) of 13. Investigations showed direct hyperbilirubinemia and AKI. After ruling out viral and autoimmune causes, DILI was suspected, likely due to fluconazole and metolazone. The patient developed hepatic encephalopathy and worsening renal function. He was managed with drug withdrawal, N-acetylcysteine, hydrocortisone, and therapeutic plasma exchange. He showed significant improvement and was discharged in a fully recovered state. Conclusion: This case highlights the importance of early diagnosis and the role of therapeutic measures, including drug withdrawal and plasma exchange, in managing DILI with systemic complications. Clinical significance: This case underscores the importance of careful drug history assessment, the utility of Roussel Uclaf Causality Assessment Method (RUCAM) for causality evaluation, and the effectiveness of plasma exchange in treating severe DILI with complications like hepatic encephalopathy and AKI.