Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread. Display omitted •CKMT1 has context-dependent roles in primary breast tumor growth and metastasis•CKMT1 upregulation promotes breast cancer cell viability and primary tumor growth•CKMT1 downregulation elevates ROS levels, which increases cell migration and invasion•CKMT1 knockdown-induced ROS release upregulates adhesion and degradative factors Ayyappan et al. investigated the role of CKMT1 in breast cancer progression and showed that CKMT1 upregulation increases tumor cell growth and viability, while downregulation promotes metastasis. This context-dependent role is tied to CKMT1-mediated regulation of the mitochondrial permeability transition pore, which modulates reactive oxygen species release.