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Breast malignant phyllodes tumor (MPT) is a fibroepithelial neoplasm characterized by high recurrence rates. Currently, no effective therapeutic agents are available, and surgery remains the mainstay of treatment for MPT. Niclosamide ethanolamine (NEN), an antiparasitic agent, has recently demonstrated broad-spectrum antitumor activity against various solid malignancies. This study aimed to evaluate the antitumor efficacy of NEN against MPT and elucidate the underlying molecular mechanisms. The effects of NEN on MPT cell proliferation and migration were assessed using CCK-8, wound healing, and Transwell migration assays. Ultrastructural alterations following NEN treatment were examined by transmission electron microscopy. Bioinformatics analyses, quantitative real-time PCR (qPCR), Western blotting, and immunofluorescence staining were employed to investigate the molecular mechanisms underlying NEN-mediated modulation of autophagy and lysosomal function. NEN significantly inhibited MPT cell proliferation and migration. Transmission electron microscopy revealed the accumulation of numerous autolysosomal structures in NEN-treated cells. Mechanistically, NEN suppressed mTOR phosphorylation, promoted nuclear translocation of transcription factor EB (TFEB), and induced lysosomal biogenesis. However, lysosomal function was compromised, as evidenced by elevated luminal pH, impaired cathepsin D maturation, and lysosomal membrane permeabilization, ultimately resulting in autophagic flux blockade at the degradation stage. Furthermore, lysosomal cathepsin leakage activated the mitochondrial apoptotic pathway, culminating in caspase-3-dependent apoptosis. NEN effectively kills MPT cells by inducing "lysosomal biogenesis-function uncoupling." This study is the first to reveal a novel anti-MPT mechanism that targets the mTOR-TFEB-lysosome axis and disrupts lysosomal homeostasis, providing a potential drug candidate for the treatment of MPT.