The most prevalent types of lymphomas are B cell lymphomas (BCL). Newer therapies for BCL have improved the prognosis for many patients. However, approximately 30% with aggressive BCL either remain refractory or ultimately relapse. These patients urgently need other options. This study shows how calcium/calmodulin-dependent protein kinase II delta (CAMKIIδ) is pivotal for BCL development. In BCL cells, ablation of CAMKIIδ inhibits both lipolysis from lipid droplets and oxidative phosphorylation (OXPHOS). With lipolysis blocked, BCL progression is markedly suppressed in two distinct BCL mouse models: MYC-driven EµMyc mice and Myc/Bcl2 double-expressed mice. When CAMKIIδ is present, it destabilizes transcription factor Forkhead Box O3A (FOXO3A) by phosphorylating it at Ser7 and Ser12. This then permits transcription of downstream gene IRF4 - a master transcription factor of lipid metabolism. The CAMKIIδ/FOXO3A axis bolsters lipid metabolism, mitochondrial respiration, and tumor fitness in BCL under metabolic stress. This study also evaluates Tetrandrine (TET), a small molecule compound, as a potent CAMKIIδ inhibitor. TET attenuates metabolic fitness and elicits therapeutic responses both in vitro and in vivo. Collectively, this study highlights how CAMKIIδ is critical in BCL progression. The results also pave the way for innovative therapeutic strategies for treating aggressive BCL.