Thyroid hormone receptor beta (TRβ, THRB) is a master transcriptional regulator of metabolism, orchestrating carbohydrate, lipid, and cholesterol pathways1. The recent approval of the TRβ-selective agonist Resmetirom for fatty liver disease and Metabolic dysfunction–Associated Steatohepatitis (MASH) underscores the clinical relevance of TRβ modulation2. Here, we demonstrate that a TRβ-fatty acid metabolism axis is conserved across breast cancers but is differentially rewired between triple-negative breast cancers (TNBC) and estrogen receptor-positive (ER+) subtypes. Short hairpin RNA (shRNA)-mediated knockdown of THRB reduced proliferation, migration and tumorgenicity in TNBC cell lines, PDX cells and mouse xenografts, whereas in ER+ breast cancer, depletion of THRB had no significant effects. In contrast, pharmacologic activation of TRβ with Resmetirom enhanced tumorigenicity of TNBC subtypes by increasing serial tumour spheroid formation in TNBC cell lines and PDX cells. Oral administration of Resmetirom in mice induced significant outgrowth of HCC1806 TNBC xenografted tumours. Mechanistically, ablation of THRB in TNBCs reduced metabolic programs, an emerging hallmark in cancers. Collectively, these findings illuminate the significance of TRβ-fatty acid metabolism in TNBC pathogenesis and identify it as a potential therapeutic target. Additionally, our findings highlight a possible deleterious effect of clinically prescribed TRβ agonist medications in promoting TNBC tumour progression.