Melanoma is known for its high metastatic potential and aggressive growth. Recurrence is common post-surgery, sometimes leading to unresectable disease. Locally recurrent unresectable melanoma of extremity has been treated with high-dose anticancer chemotherapy via isolated limb perfusion (ILP) to improve local efficacy of drug and salvage limbs. Standard ILP monitoring uses radiolabeled dyes, requiring specialized personnel and involving radiation exposure. In this case, we used indocyanine green (ICG) to track systemic drug leakage during ILP. A 47-year-old gentleman with recurrent malignant melanoma of the left foot, operated twice earlier and treated with adjuvant pembrolizumab, presented with multiple in-transit metastases in the limb. ILP was planned, with 5 mg ICG administered in the perfusion solution along with high-dose melphalan. Stryker’s SPI PHI handheld device was employed to visualize ICG during ILP. Absence of fluorescence beyond the involved extremity, such as fingers, ears, and the abdominal wall, indicated no systemic drug dispersion. For control, technetium radiocolloid dye was co-administered, monitored by a precordial gamma probe, confirming no systemic leakage, and validating effectiveness of ICG in leakage monitoring. ICG proves to be a safe, reliable, cost-effective, radiation-free approach for precise systemic drug leakage monitoring during ILP for recurrent melanoma of extremity.