Purpose: MORC4 has recently been characterized as a breast cancer-associated antiapoptotic oncoprotein. In the current study, we explored its downstream regulation in luminal A/B breast tumors. Materials and Methods: Bioinformatic prediction was performed using data from The Cancer Genome Atlas (TCGA)-breast cancer (BRCA). Cellular and molecular studies were conducted using luminal A/B representative MCF-7 and BT-474 cell lines. Results: ENST00000355610.8 (encoding MORC4a isoform) was the dominant transcript in breast cancer. ChIP-qPCR and dual-luciferase assay confirmed two STAT3-binding sites in the MID2 promoter in both MCF-7 and BT-474 cells. Co-IP confirmed an interaction between MORC4 and STAT3. ChIP-qPCR data indicated that MORC4 inhibition led to remarkably decreased enrichment of the STAT3-binding MID2 promoter segments. MORC4 overexpression significantly elevated BCL-2 expression in MCF-7 cells and increased their resistance to adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP). MID2 inhibition largely abrogated MORC4-induced drug-resistance. However, the drug-resistant phenotype was rescued by overexpressing MID2-MT that was resistant to MID2 siRNA. Conclusion: This study revealed a novel regulatory mechanism of MORC4 on MID2 expression via STAT3-mediated transcriptional activation. This regulatory axis might confer increased chemoresistance to breast cancer cells.