Cutaneous T-cell lymphomas (CTCL), including mycosis fungoides (MF) and Sézary syndrome (SS), are rare hematological malignancies with limited curative treatment options. Despite early-stage responsiveness, these malignancies often relapse in advanced stages, highlighting the need for novel, durable therapies. As other non-Hodgkin lymphoma (NHL) MF and SS have a greater incidence rate in males than females. The endocrine contribution to this gender difference is unknown. Although several studies could show a potential role of ERβ on NHL lymphomagenesis, its impact on CTCL development is unknown. In this study, we investigated LY500307, a selective ERβ agonist, as a potential treatment for CTCL. Our results show that LY500307 selectively reduced the viability of CTCL cells, sparing non-cancerous skin cells. LC-MS/MS analysis revealed that CTCL cells accumulated significantly higher concentrations of LY500307 compared to normal skin cells, likely contributing to its selective cytotoxicity. Mechanistically, LY500307 induced apoptosis, G2/M cell cycle arrest, and increased sensitivity to chemotherapeutic agents, particularly MMAE. Furthermore, LY500307 treatment significantly reduced tumor growth in a CTCL xenograft mouse model without notable toxicity. These findings suggest LY500307 as a promising therapeutic agent for CTCL, warranting further clinical investigation, including the potential for topical applications.