The ion exchange reaction has been extensively used in the field of synthesis of functionalized supramolecular materials such as layered double hydroxides (LDHs), ion-embedded batteries, sewage disposal and so on. In this work, the factors influencing the anion exchange behavior in the LDH gallery, such as the exchange domain, the exchange order, the driving force, and the diffusion of the anions, are investigated systematically using molecular dynamics (MD) simulations and density functional theory (DFT) methods in view of both thermodynamics and dynamics. 159 models of M^II_RAl-A-LDHs (M^II = Mg, Ni, Zn; R = 1.4–8, A = OH⁻, Cl⁻, Br⁻, NO₃⁻, HCOO⁻, C₆H₅SO₃⁻, CO₃²⁻, SO₄²⁻, and PO₄³⁻, respectively) are calculated. The results reveal that the anion exchange domain (interlayer distance) in LDHs is determined not only by the size and their arrangement modes of the guest anions, but also by the charges the anions carry. The relative binding energies of different anions and the Gibbs free energy changes of the anion exchange reactions in LDHs decrease in the order of PO₄³⁻ > CO₃²⁻ > SO₄²⁻ > OH⁻ > Cl⁻ > Br⁻ > HCOO⁻ > NO₃⁻ > C₆H₅SO₃⁻, which is in accordance with the experimental anion exchange order. The stronger the hydrogen bonding between the anion and the host, the larger the charge transfer, and the smaller the electronegativity of the anion, the more difficult it is for the anion to be exchanged out from LDH interlayer. In addition, for the anions with the same charges, the relative binding energy is linearly well correlated with the interlayer spacing. By analyzing the contribution of each energetic item comprising the total potential energy, it is found that the major driving force of anion exchange is the electrostatic force. The diffusion coefficient (D) along the c direction is nearly equal to zero, suggesting that the diffusion of anions occurs mainly in the ab plane of the LDH cell. It also can be inferred that when the cell parameter c < 24.0 Å, the anion exchange order is mainly determined by the thermodynamic factors, whereas when c > 24.0 Å, both the thermodynamic and the dynamic factors cast the same effect on the anion exchange behavior. This work provides an in-depth understanding of the anion exchange behavior, and is helpful guidance for the design and synthesis of functionalized guest anion intercalated LDHs and related materials using the anion-exchange method.