Molecular dynamics (MD) simulations have been applied to study the interactions between hydrophobic and hydrophilic faces of ordered cellulose chains and a single layer of graphene in explicit aqueous solvent. The hydrophobic cellulose face is predicted to form a stable complex with graphene. This interface remains solvent-excluded over the course of simulations; the cellulose chains contacting graphene in general preserve intra- and interchain hydrogen bonds and a tg orientation of hydroxymethyl groups. Greater flexibility is observed in the more solvent-exposed cellulose chains of the complex. By contrast, the hydrophilic face of cellulose exhibits progressive rearrangement over the course of MD simulations, as it seeks to present its hydrophobic face, with disrupted intra- and interchain hydrogen bonding; residue twisting to form CH-π interactions with graphene; and partial permeation of water. This transition is also accompanied by a more favorable cellulose–graphene adhesion energy as predicted at the PM6-DH2 level of theory. The stability of the cellulose–graphene hydrophobic interface in water exemplifies the amphiphilicity of cellulose and provides insight into favored interactions within graphene–cellulose materials. Furthermore, partial permeation of water between exterior cellulose chains may indicate potential in addressing cellulose recalcitrance.