The environmental implications of graphene have received much attention, however, little is known about how graphene affects or may be affected by the enzymatic reactions that are critically involved in natural organic matter transformation processes. We conducted experiments to examine the role of few-layer graphene (FLG) in the reaction system of tetrabromobisphenol A (TBBPA) mediated by horseradish peroxidase (HRP). We found that TBBPA was transformed by HRP into two products that were likely formed from coupling of two TBBPA radicals via interaction of an oxygen atom on one radical and a propyl-substituted aromatic carbon atom on the other. Presence of FLG greatly increased the reaction rate by protecting HRP from inactivation. Direct reactions between TBBPA radicals and FLG were unequivocally evidenced using (14)C labeling and the characteristic photoelectron response of bromine contained in TBBPA. The thickness, size, and aggregation profile of FLG was modified by the reaction as shown by multiple characterization tools. Assessment using Daphnia magna revealed a substantial decrease in the bioaccumulation and toxicity of the FLG after being modified. The data provides the first evidence that FLG can be modified in HRP-mediated reactions and indicates that such modifications may have strong implications in its ecological effects.