Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options. PANoptosis, a newly identified programmed cell death pathway, offers therapeutic strategies for TNBC. ACY-1215 has demonstrated preliminary efficacy in patients with TNBC and HR+/HER2- metastatic breast cancer. However, its moderate target engagement and suboptimal selectivity may limit its clinical efficacy. In this study, a series of potent HDAC6-selective inhibitors bearing a 5-pyrazolyl-benzotriazole scaffold has been developed. Compound TNI-97 demonstrated potent HDAC6 inhibitory activity and great isoform selectivity. TNI-97 elicited PANoptotic cell death in MDA-MB-453 cell models in vitro and in vivo. TNI-97 exhibited a TGI of 91% in MDA-MB-453 CDX as monotherapy and a TGI of 92% in 4T1 CDA when combined with paclitaxel. The discovery of TNI-97 holds promise for the development of more potent HDAC6 inhibitors as PANoptotic inducers and TNBC drug candidates.