The ubiquitin-proteasome system (UPS) precisely controls the levels of most proteins in a cell. As such, the UPS regulates cellular processes such as proliferation and survival and is dysregulated in a variety of diseases including cancer. Lymphoid malignancies are the fourth most common cancer and the sixth leading cause of cancer deaths in the United States. Proteasomal inhibition has had clinical success in treating mature B-lymphoid cancers, positioning the UPS as a rational therapeutic target in these diseases. As standard therapies for mature B-cell cancers fail to provide long-term cures in a large proportion of patients, there is a need for continued research in this field. Here, we assessed the role of the UPS E3 ligase FBXW7 in mature B-cell neoplasms. Coupling proteomic screens and biochemistry, we report for the first time that FBXW7 is an E3 ligase for the lysine methyltransferase KMT2D. We show that FBXW7 utilizes its conserved WD40 domain to interact with KMT2D. KMT2D contains a stretch of N-terminal phosphodegron repeats that mediate interaction with FBXW7. These phosphodegrons are phosphorylated in cells and phosphorylation is required for KMT2D to interact with FBXW7. FBXW7 functions as a bona fide E3 ubiquitin ligase for KMT2D in mediating K48-linked ubiquitination and proteasomal degradation of KMT2D. Using both in vitro and in vivo functional studies, we uncover an important role for the FBXW7-KMT2D axis in mature B-cell cancer cells. The FBXW7-KMT2D degradation axis regulates mitochondrial function and genes related to oxidative phosphorylation (OXPHOS) in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) cells. Consistently, loss of FBXW7 inhibits DLBCL cell growth and further sensitizes these cells to OXPHOS inhibition. Our findings elucidate a novel mechanism of regulation of KMT2D protein levels by the ubiquitin-proteasome pathway and uncover a role for FBXW7 as a positive regulator of mature malignant B-cells, where inhibition of FBXW7 may serve as a therapeutic vulnerability in these cancers.