Hyaluronan (HA) is a major component in the extracellular matrix and is responsible for maintaining the water content of the skin. However, the function and moisturizing mechanism at the atomic level of HA remain only partially understood. Investigating the interactions of HA and other skin components can help us understand how the former moisturizes the skin. Considering that aquaporin-3 (AQP3) is a protein responsible for transmembrane water transport in the human skin, we have, therefore, investigated the interactions of AQP3 and HA with different molecular weights using molecular dynamics simulations in the present work. Our results indicate that HA can adsorb onto AQP3 and decrease water mobility around the latter. In addition, the permeation rate of water through AQP3 can also be decreased by HA, and this phenomenon is particularly obvious for small molecular HA. Moreover, we found that large molecular HA can link two adjacent membranes in the extracellular matrix, increasing the adhesion between the membranes in the periplasm. The results of the present study indicate that HA is a natural regulator of AQP3, revealing the synergetic function of HA and AQP3 in the extracellular matrix of the skin.