Cadmium (Cd) is found widely in soil and is severely toxic for plants, causing oxidative damage in plant cells because of its heavy metal characteristics. The DNA damage response (DDR) is triggered in plants to cope with the Cd stress. The DNA mismatch repair (MMR) system known for its mismatch repair function determines DDR, as mispairs are easily generated by a translesional synthesis under Cd-induced genomic instability. Cd-induced mismatches are recognized by three heterodimeric complexes including MutSα (MSH2/MSH6), MutSβ (MSH2/MSH3), and MutSγ (MSH2/MSH7). MutLα (MLH1/PMS1), PCNA/RFC, EXO1, DNA polymerase δ and DNA ligase participate in mismatch repair in turn. Meanwhile, ATR is preferentially activated by MSH2 to trigger DDR including the regulation of the cell cycle, endoreduplication, cell death, and recruitment of other DNA repair, which enhances plant tolerance to Cd. However, plants with deficient MutS will bypass MMR-mediated DDR and release the multiple-effect MLH1 from requisition of the MMR system, which leads to weak tolerance to Cd in plants. In this review, we systematically illustrate how the plant DNA MMR system works in a Cd-induced DDR, and how MMR genes regulate plant tolerance to Cd. Additionally, we also reviewed multiple epigenetic regulation systems acting on MMR genes under stress.