Protein degradation pathways are critical for maintaining proper protein dynamics within the cell, and considerable efforts have been made toward the development of therapeutics targeting these catabolic processes. We report here that isoginkgetin, a naturally derived biflavonoid, sensitized cells undergoing nutrient starvation to apoptosis, induced lysosomal stress, and activated the lysosome biogenesis gene TFEB. Isoginkgetin treatment led to the accumulation of aggregates of polyubiquitinated proteins that colocalized strongly with the adaptor protein p62, the 20S proteasome, and the endoplasmic reticulum-associated degradation (ERAD) protein UFD1L. Isoginkgetin directly inhibited the chymotrypsin-like, trypsin-like, and caspase-like activities of the 20S proteasome and impaired NF-B signaling, suggesting that the molecule may display its biological activity in part through proteasome inhibition. Importantly, isoginkgetin was effective at killing multiple myeloma (MM) cell lines in vitro and displayed a higher rate of cell death induction than the clinically approved proteasome inhibitor bortezomib. We propose that isoginkgetin disturbs protein homeostasis, leading to an excess of protein cargo that places a burden on the lysosomes/autophagic machinery, eventually leading to cancer cell death.