In this study, the effect of enzymatic pre-treatment and the size of cassava tubers on mechanical peeling was examined. Cassava tubers were sorted based on their mass as small, medium and large. Viscozyme® L and an abrasive cassava peeling machine was used for the enzymatic pre-treatment and the mechanical peeling, respectively. Response surface methodology (RSM) was used to investigate the effect of the enzyme dose (0.5–1.9 mL g−1), incubation time (1.5–6 h), peeling time (1.5–4.5 min) and size of the tubers (small, medium and large) on the peeling process. Peeled surface area (PSA) and peel loss (PL) were measured as main responses in RSM. Results showed that the PSA and PL were significantly (p < 0.05) influenced by the enzyme dose, incubation time and peeling time. The size of tubers only had a significant impact on the PSA. The optimum operating conditions for different sizes of tubers were found and validated. Under optimum conditions, the PSA of the large tubers (89.52%) was significantly higher than the PSA of the medium and small tubers (p < 0.05). Application of enzymatic pre-treatment can improve the mechanical peeling process especially for larger cassava tubers.