Drug resistance and relapse are the major obstacles in multiple myeloma (MM) treatment, driving the search for novel therapeutics. The chemoactivation of mitochondrial caseinolytic protease P (ClpP) has shown to have anticancer effects on many tumors, but has seldom been elucidated in MM. Here we found that the CLPP expression was elevated in MM patients, and further increased in relapsed cases. After synthesizing and screening a panel of ClpP agonists, we identified a compound, 7b, as the most potent anti-MM agent in vitro. 7b activated ClpP protease activity, selectively degrading mitochondrial proteins, many of which are involved in oxidative phosphorylation (OXPHOS). As result, 7b treated MM had metabolic dysfunction, the mitochondrial membrane potential (MMP) collapse, reduced OXPHOS levels, and increased mitochondrial reactive oxygen species (ROS), leading to mitophagy-mediated MM cell death. Notably, 7b also showed efficacy against drug-resistant MM cell lines, including bortezomib- and lenalidomide-resistant cells. In vivo, 7b also exhibited remarkable anti-MM activity with tolerable side effects. In conclusion, targeting ClpP represents a promising therapeutic strategy for MM, with 7b serving as a potent anti-MM agent, especially for relapsed and refractory MM.Copyright © 2025. Published by Elsevier Inc.