(1) Background and aim: Multimodal treatment is the current standard approach for managing lymphedema, with the goal of normalizing or reducing volume discrepancies, improving function, and enhancing appearance. However, following the reduction of the solid component and enhancement of lymph flow through physiological procedures involving supermicrosurgery, residual areas of fibrosis or lipodystrophy may persist, causing dissatisfaction for both the patient and the physician. (2) Methods: We present a three-case series of lymphedema, two affecting the upper limb and one affecting a lower limb, all previously treated with lymphaticovenular anastomosis (LVA) and/or debulking liposuction, which resulted in satisfactory overall volume reduction of the limbs, but with persistent swelling of the dorsum of the hand and forefoot, respectively. All patients were subsequently treated with a combination of bioengineered enzymatic cocktail (BEC). (3) Results: All three patients demonstrated stable reduction of swelling in the affected areas at one-month follow-up, with improved quality of life and function, which was maintained at six months followup. (4) Conclusion: These preliminary observations suggest that multi-enzyme cocktails warrant investigation as adjuncts for localized, post-surgical residual lymphedema, particularly for distal, anatomically challenging regions, such as the hand, foot, and digits, where surgical options are limited.