Coordinated regulation of autophagy and apoptosis helps to enhance the antitumor effects of sodium selenite. However, the potential molecules that act as switch nodes in the crosstalk between autophagy and apoptosis is still elusive. Phospholipid scramblase 1 (PLSCR1) has been shown to regulate leukocyte differentiation, while its role in autophagy/apoptosis toggle switch remains unexplored. In this study, we showed that sodium selenite switched protective autophagy to apoptosis in p53-wild type NB4 cells without obvious caspase-8/apoptosis-inducing factor (AIF) axis activation, while induced autophagy-dependent caspase-8/AIF axis activation in p53-mutant Jurkat cells. Additionally, p53 was demonstrated as a positive regulator of PLSCR1. p53-dependent up-regulation of PLSCR1 accounted for the differential regulation of autophagy and apoptosis induced by sodium selenite. Furthermore, sodium selenite induced the release of AIF from mitochondria to cytosol with the facilitation of caspase-8 in Jurkat cells, while not in NB4 cells. The released AIF further enhanced autophagy flux through interacting with PLSCR1, which hereby resulting in the disassociation of PLSCR1 from Atg5-Atg12 complex. Our results indicate that PLSCR1 plays a critical role in p53-dependent regulation of autophagy and apoptosis in sodium selenite-treated leukemia cells. Manipulation of p53-PLSCR1 cascade might be beneficial to enhance the anti-tumor effects of sodium selenite. Copyright © 2020 Elsevier Inc. All rights reserved.