Short- and long-term hand function was evaluated in adult patients with deep dermal and full-thickness hand burns after treatment with enzymatic debridement (NexoBrid^® MediWound Ltd., Yavne, Israel), assessing the results at discharge and 3, 6, and 12 months post-burn. This prospective cohort study was performed in the Burn Center in Beverwijk between March 2017 and December 2019. Hand function was assessed using Modified Kapandji Index scores, the Jebsen-Taylor Hand Function Test, and range of motion; scar quality using the Patient and Observer Scar Assessment Scale version 2.0; and quality of life using the Quick Disability Arm Shoulder Hand Questionnaire and the Canadian Occupational Performance Measure. Ten patients (14 hand burns) were included. The need for a skin graft after NexoBrid^® was 86%, and 50% needed additional surgical excision before skin grafting. Digits 3 and 4 achieved near-to-normal total active motion, and at least 50% of the hands achieved a normal range within the Jebsen-Taylor Hand Function Test in four items at 12 months post-burn. Scar quality and quality of life improved significantly over time. The present study can be considered as a proof-of-concept study for future clinical trials on enzymatic debridement for hand burns.