Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking ER, PR, and HER2 expression, with limited targeted therapies and poor outcomes. Epigenetic dysregulation, particularly aberrant DNA methylation, is a key driver. Decitabine, a DNA methyltransferase inhibitor (DNMTi), shows promise by reactivating silenced tumor suppressor genes and modulating immune responses. This systematic review evaluates preclinical and clinical evidence on decitabine’s efficacy, mechanisms, and translational potential in TNBC. Methods: A PRISMA-2020 compliant search of PubMed, EBSCO, Web of Science, and Semantic Scholar was conducted up to April 2025. Included studies assessed decitabine alone or in combination in TNBC preclinical or clinical settings. Risk of bias was assessed using QUIPS and RoB 2.0 tools. Results: Twenty-five studies were included. In vitro, decitabine-induced growth inhibition, apoptosis, and re-expression of silenced genes (such as BRCA1 and CDH1). In vivo, it reduced tumor burden and enhanced anti-tumor immunity through MHC-I, PD-L1, and STING pathway upregulation. Synergy was noted with anti-PD-1, HDAC inhibitors, and chemotherapy. Resistance mechanisms included persistent DNMT activity, low DCK, and miRNA-driven escape (miR-155–TSPAN5). Conclusions: Decitabine demonstrates strong preclinical and early clinical potential in TNBC via epigenetic reprogramming and immune activation. Future strategies should focus on biomarker-based selection and resistance mitigation.