Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA and LDHB are two main LDH subunits, and both are frequently overexpressed in tumors and essential for tumor growth. A number of LDHA/B small-molecule inhibitors have been developed. Here, we report the discovery of the first LDH proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105). 22 potently degraded LDHA in a time- and ubiquitin-proteasome system-dependent manner. Using an unbiased global proteomic study, we confirmed that 22 degraded both LDHA and LDHB significantly. 22 was significantly more potent than the parent LDH inhibitor in suppressing the growth of both quasi-mesenchymal state and epithelial state pancreatic cancer cell lines. Furthermore, 22 was bioavailable in mice through intraperitoneal injection. Overall, 22 could be a valuable chemical tool for the research community to explore pathophysiological functions of LDH in vitro and in vivo.