Tumor cells often hijack endoplasmic reticulum (ER) mediated signaling to facilitate tumor progression by adapting to the cellular stress evoked by oncogene overexpression and adverse microenvironment. Despite the prevalence of MYC-driven cancers, how the MYC oncoprotein regulates ER stress response pathways during tumorigenesis remains incompletely understood. Here we show that MYC drives continuous upregulation of ubiquitin fusion degradation 1 (UFD1) during T-cell acute lymphoblastic leukemia (T-ALL) development. As the E2 component of an ER-associated degradation (ERAD) complex, UFD1 facilitates the elimination of misfolded/unfolded proteins from the ER. We found that genetic and pharmacological disruption of UFD1 function exacerbates ER stress and activates the unfolded protein response (UPR). Specifically, UFD1 knockdown in human T-ALL cells impairs ERAD and promotes the proapoptotic UPR through the PERK-CHOP-BCL2 axis. This effect is demonstrated by an upregulation of PERK, phospho-PERK and its downstream effector CHOP, as well as a downregulation of BCL2 and BCLxL. Indeed, CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor-cell apoptosis induced by UFD1 knockdown. Allelic loss of ufd1 in zebrafish similarly induces tumor-cell apoptosis and impairs MYC-driven T-ALL progression without affecting general animal health. These studies establish the UFD1-mediated ER stress response as an important mediator of MYC-driven tumor progression and suggest strategies for targeted therapy in T-ALL, and perhaps other MYC-driven cancers. Although UFD1-specific inhibitors have yet to be developed, inhibitors that target the p97 co-factor in UFD1-mediated ERAD are readily available. Importantly, we show that treatment with CB-5083, a selective and oral bioactive inhibitor of p97, can effectively kill human MYC-overexpressing T-ALL patient cells ex vivo and inhibits tumor progression in zebrafish models of MYC-driven T-ALL. Thus, CB-5083 treatment may represent an effective targeted therapy for T-ALL, especially relapsed/refractory ones with gain-of-function NOTCH1 mutations and thus MYC-overexpression.