Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) and lacks effective treatment options. Polyphyllin B (PB), a saponin extracted from Paris formosana Hayata, has shown potential in cancer therapy. However, its anti-TNBC effects and mechanisms are not well studied. This study investigated the effects and underlying mechanisms of PB in TNBC. Methods CCK8 assay, Wound healing assay, Transwell migration experiments, and clonogenic assay were performed to assess the effects of PB in three TNBC cells lines. Iron level, lipid ROS, and MDA levels were assessed as ferroptosis markers. Mechanistic studies were conducted using molecular docking, Western blot, immunofluorescence, RT-qPCR, Nrf2 overexpression assays and establishment of a TNBC mouse model. Results PB treatment resulted in significant cell death and inhibited the migration of TNBC cells. Accumulation of iron and MDA suggested that PB induces ferroptosis. In vitro and in vivo , PB downregulated the expression of nuclear factor E2-related factor 2 (NRF2) and sequestosome-1 (P62) and upregulated the expression of Kelch-like ECH-associated protein 1 (KEAP1). Furthermore, it modulated the expression of key ferroptosis regulators, including acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). In a TNBC mouse model, PB suppressed tumor growth and increased malondialdehyde accumulation. Conclusion PB inhibits cell proliferation and migration and induces ferroptosis in TNBC through the inactivation of NRF2. PB is a promising candidate for TNBC treatment that warrants further investigation.