Liquid-phase exfoliation (LPE) is the best-known method for the synthesis of two-dimensional (2D) nanosheets. Compared to enthalpy, entropy is hardly considered to be a factor in choosing energy-efficient solvents and has not even been verified to be negligible. In this Letter, we explore the entropy contribution in LPE by performing molecular dynamics (MD) simulation of the structural flexibility effect in graphene, hexagonal boron nitride (hBN), and molybdenum disulfide (MoS2). Our results show that surface vibration favors the exfoliation of graphene and hBN and destabilizes the reaggregation of nanosheets in water at 300 K, whereas the opposite is found for MoS2. The entropy change is found to be 41%, 48%, and 4% of the enthalpy gain for graphene, hBN, and MoS2 in LPE, respectively, and 64%, 32%, and 56% in reaggregation, which amounts to a step advancement for solvent screening in LPE of 2D materials.