The internal and external mass migration and redistribution of the Earth system are usually accompanied by changes in the gravity field, and the Gravity Recovery and Climate Experiment (GRACE) has been proven to be able to effectively monitor and evaluate such changes. The Chile Triple Junction (CTJ) is the convergence point of the Nazca plate, the Antarctic plate and the South American plate. Subductions of different forms and rates in the north and south of the CTJ have varying degrees of impact on the surface and underground material changes of the South American plate. In this study, GRACE data are used in the estimation of the comprehensive mass changes in the South America Continent (SAC) Near the CTJ (~15° range). In addition, surface movement changes constrained by GNSS data cannot fully explain the GRACE results after deducting hydrological information, which indicates that residual signals might be attributed to mass changes beneath the crust, that is, the Moho interface deformation. After eliminating surface movement and hydrological signals from the comprehensive mass changes of GRACE, this study obtains the deep structural information and calculates the Moho changes of three significant regions with rates of −2.12 ± 0.67 cm/yr, 0.18 ± 0.19 cm/yr and −6.46 ± 1.31 cm/yr, respectively. Results have demonstrated that the subductions of the Nazca plate and the Antarctica plate have an effect on the uneven deformation of the Moho interface beneath the SAC. The Moho beneath the SAC mainly shows a deepening trend, but it is uplifted in some areas north of CTJ. On the whole, the rate of Moho changes is greater in the south than in the north. The relationship between Moho changes and surface changes also indicates that a longer timescale may be needed for maintaining isostatic balance.