Trastuzumab‐emtansine (T‐DM1) is an antibody‐drug conjugate that has been approved for the treatment of human epidermal growth factor receptor 2 (HER2)‐positive metastatic breast cancer. Despite the remarkable efficacy of T‐DM1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT‐474/KR cells, a T‐DM1‐resistant cell line established from HER2‐positive BT‐474 breast cancer cells, as a model to investigate mechanisms of T‐DM1 resistance and explore effective therapeutic regimens. We show here for the first time that activation of signal transducer and activator of transcription 3 (STAT3) mediated by leukemia inhibitory factor receptor (LIFR) overexpression confers resistance to T‐DM1. Moreover, secreted factors induced by activated STAT3 in resistant cells limit the responsiveness of cells that were originally sensitive to T‐DM1. Importantly, STAT3 inhibition sensitizes resistant cells to T‐DM1, both in vitro and in vivo, suggesting that the combination T‐DM1 with STAT3‐targeted therapy is a potential treatment for T‐DM1‐refractory patients.