BACKGROUND: Peroxiredoxin 6 (PRDX6) scavenges reactive oxygen species (ROS) and plays a key role in antioxidant defense. Although PRDX6 is involved in various cancers, its role in breast cancer (BRCA) remains unclear. METHODS: Cell proliferation was assessed using CCK-8, EdU staining, and colony formation assays. Migration and invasion were evaluated via wound-healing and transwell assays. ROS levels and mitochondrial membrane potential were measured by fluorescence microscopy or flow cytometry. Oxidative phosphorylation (OXPHOS) activity was determined by ATP production and NAD(+)/NADH ratio. Mitochondria were visualized by TEM, and mitochondrial complex subunits were detected by quantitative real-time PCR and Western blotting. In vivo effects were evaluated using a xenograft tumor model. RESULTS: Although PRDX6 was downregulated in BRCA overall, it showed elevated expression in aggressive subtypes and advanced-stage tumors, correlating with poor prognosis. Overexpression of PRDX6 enhanced BRCA cell proliferation, migration, and invasion. PRDX6 reduced ROS levels, upregulated mitochondrial transcription factor A (TFAM) expression, and promoted mitochondrial complex subunit expression and OXPHOS. Inhibition of TFAM led to a decrease in the expression of some of the mitochondrial complex subunits, which reversed the pro-carcinogenic phenotype of the tumor. PRDX6 also promoted tumor growth in vivo. CONCLUSION: PRDX6 maintains intracellular homeostasis by reducing ROS and promotes mitochondrial biogenesis and OXPHOS through TFAM-dependent and -independent pathways, driving BRCA progression.