The distribution and clearance of graphene materials as drug delivery systems at organ and suborgan levels over the long term remain unclear. Here we compared the fate of 14C-labeled few-layer graphene with different lateral sizes in mice after one intravenous injection for up to 1 year and demonstrated that few-layer graphene mainly accumulated in the liver, and larger graphene can be degraded into 14CO2 by Kupffer cells. The mechanism involves the uptake of graphene by liver cells, larger graphene-induced membrane perturbation of red blood cells, and enhanced erythrophagocytosis by the Kupffer cells, resulting in the degradation of hemoglobin into hemes and a rise in iron concentrations in cells. The increased iron triggered a Fenton reaction to generate the hydroxyl radical, facilitating the degradation of larger graphene into 14CO2. Our findings propose a mechanism for the transformation of graphene that significantly contributes to our understanding of the hepatic fate of graphene in vivo.