As a widely used first-line agent for prostate cancer treatment, cisplatin is facing drug resistance which has resulted in chemotherapy failure in many prostate cancer patients, while the related molecular mechanisms remain unclear. In this study, we discovered that MEIS homeobox 2 (MEIS2) was lowly expressed in prostate cancer tissues by bioinformatics analysis, which had a close connection with the T stage and N stage of the tumor. Cell function experiments demonstrated that MEIS2 overexpression was capable of significantly suppressing proliferation of tumor cells, arresting prostate cancer cells in G0/G1 phase, and promoting DNA damage, thereby enhancing the sensitivity of prostate cancer to cisplatin. Dual-luciferase assay and chromatin co-immunoprecipitation (ChIP) assays confirmed the binding relationship between MEIS2 and ELF1. The results of rescue assay showed that ELF1 could promote DNA damage and enhance the sensitivity of tumor cells to cisplatin by activating MEIS2. In conclusion, the results of this study demonstrated that ELF1 could modulate DNA damage through activating MEIS2 and thus enhance cisplatin sensitivity in prostate cancer. This study suggested that the ELF1/MEIS2 axis may be a therapeutic target to strengthen cisplatin sensitivity in prostate cancer.