In this study, molecular dynamics simulations were used to investigate the effects of interfacial dynamics and nanoconfinement on the cluster characteristics and aggregation mechanisms of CaSO4 solutions inside two-dimensional (2D) nanochannels. Results reveal that CaSO4 clusters with low hydration are more likely to be found in 2D nanochannels than in a bulk solution. The interface region formed by layered water molecules results in the specific ion distributions inside a 2D nanochannel, affecting the hydration dynamics of Ca2+ ions near the interface region and ion-association characteristics. When Ca2+ ions migrate from the interface region to the bulk-like region, the association of Ca2+ and SO42− ions is promoted and the water exchange around CaSO4 clusters is enhanced, benefiting the formation of CaSO4 clusters with Ca2+ ions in high coordinated and low hydration degrees. Our results offer a microscopic understanding of the characteristics of prenucleation clusters and aggregation mechanisms in CaSO4 solutions inside 2D nanochannels, helping to control of the morphology and properties of CaSO4 precipitation.