Intracellular Mg²⁺ levels are strictly regulated; however, the biological importance of intracellular Mg²⁺ levels and the pathways that regulate them remain poorly understood. Here, we determined that intracellular Mg²⁺ is important in regulating both energy metabolism and tumor progression. We determined that CNNM4, a membrane protein that stimulates Mg²⁺ efflux, binds phosphatase of regenerating liver (PRL), which is frequently overexpressed in malignant human cancers. Biochemical analyses of cultured cells revealed that PRL prevents CNNM4-dependent Mg²⁺ efflux and that regulation of intracellular Mg²⁺ levels by PRL and CNNM4 is linked to energy metabolism and AMPK/mTOR signaling. Indeed, treatment with the clinically available mTOR inhibitor rapamycin suppressed the growth of cancer cells in which PRL was overexpressed. In Apc^Δ14/+ mice, which spontaneously form benign polyps in the intestine, deletion of Cnnm4 promoted malignant progression of intestinal polyps to adenocarcinomas. IHC analyses of tissues from patients with colon cancer demonstrated an inverse relationship between CNNM4 expression and colon cancer malignancy. Together, these results indicate that CNNM4-dependent Mg²⁺ efflux suppresses tumor progression by regulating energy metabolism.