In humans, the abnormal accumulation of proteins is strongly correlated with neurodegenerative diseases. PSMB6 is a member of the proteasome family and encodes the 20S subunit beta 6 which performs caspase-like proteasome activity. However, the biological roles of PSMB6 in neurodevelopment are poorly defined. In this study, we utilized zebrafish to construct a psmb6 knockout model. We show that the deficiency of psmb6 leads to early embryonic death, with proteasome inactivity identified as the cause of neuronal apoptosis. Although the inactivation of p53 cannot rescue the defects observed in psmb6 mutants, it delays the onset of the defective phenotypes. Thus, psmb6 plays a crucial role in early embryonic development.