The present climate simulation and future projection of the mixed layer depth (MLD) and subduction process in the subtropical Southeast Pacific are investigated based on the geophysical fluid dynamics laboratory earth system model (GFDL-ESM2M). The MLD deepens from May and reaches its maximum (>160 m) near (24°S, 104°W) in September in the historical simulation. The MLD spatial pattern in September is non-uniform in the present climate, which shows three characteristics: (1) the deep MLD extends from the Southeast Pacific to the West Pacific and leads to a “deep tongue” until 135°W; (2) the northern boundary of the MLD maximum is smoothly near 18°S, and MLD shallows sharply to the northeast; (3) there is a relatively shallow MLD zone inserted into the MLD maximum eastern boundary near (26°S, 80°W) as a weak “shallow tongue”. The MLD non-uniform spatial pattern generates three strong MLD fronts respectively in the three key regions, promoting the subduction rate. After global warming, the variability of MLD spatial patterns is remarkably diverse, rather than deepening consistently. In all the key regions, the MLD deepens in the south but shoals in the north, strengthing the MLD front. As a result, the subduction rate enhances in these areas. This MLD antisymmetric variability is mainly influenced by various factors, especially the potential-density horizontal advection non-uniform changes. Notice that the freshwater flux change helps to deepen the MLD uniformly in the whole basin, so it hardly works on the regional MLD variability. The study highlights that there are regional differences in the mechanisms of the MLD change, and the MLD front change caused by MLD non-uniform variability is the crucial factor in the subduction response to global warming.