A major cause of morbidity and mortality in multiple myeloma is kidney injury from overproduction of monoclonal immunoglobulin light chains (FLC). FLC can induce damage through the production of hydrogen peroxide, which activates pro-inflammatory and pro-apoptotic pathways. The present study focused on catalase, a highly conserved antioxidant enzyme that degrades hydrogen peroxide. Initial findings were that FLC increased hydrogen peroxide levels but also decreased catalase levels and activity in proximal tubule epithelium. In order to clarify, we showed that the phosphatidylinositol 3-kinase inhibitor, LY294002, inhibited FLC-induced Akt-mediated deactivation of Forkhead box O class 3a (FoxO3a) and increased catalase activity in proximal tubule cells. Augmented catalase activity decreased FLC-mediated production of hydrogen peroxide as well as the associated increase in High Mobility Group Box 1 (HMGB1) protein release and caspase-3 activity. Coincubation of cells with FLC and an allosteric activator of Sirtuin 1 (SIRT1) was also sufficient to increase catalase activity and promote similar cytoprotective effects. Our studies confirmed that the mechanism of downregulation of catalase by FLC involved deactivation of FoxO3a and inhibition of SIRT1. Mechanistic understanding of catalase regulation allows for future treatments that target pathways that increase catalase in the setting of proximal tubule injury from FLC.