Cell surface calreticulin (CRT) can mediate apoptotic cells removal by binding and activating LDL receptor-related protein (LRP1). Phosphatidylserine (PS) lipids in the inner leaflet of the cell membrane are externalized and become exposed in cholesterol (CHOL)-rich membrane raft-like microdomain during apoptosis and co-localized with cell surface CRT. How the apoptotic raft-like membrane microdomain affects the structure and dynamics of CRT, further affecting CRT binding with LRP1 to signal apoptotic-cell clearance, remains unknown. In this study, we investigate the interactions between CRT and raft-like bilayers with or without POPS lipids with molecular dynamics simulations. In addition, the effect of an apoptotic raft bilayer on the binding between CRT and thrombospondin-1 (TSP1), a ligand of CRT on the cell surface to signal focal adhesion disassembly, was also investigated. Results of single CRT interactions with raft-like bilayers show that PS lipids in apoptotic raft-like bilayer increased the interactions between CRT and lipid bilayer, which enhanced the conformational stability and increased dynamical motion of CRT. The microscopic and mesoscopic properties of apoptotic raft-like bilayer were altered by the binding of CRT with lipid bilayer. Results of CRT-TSP1 complex interactions with raft-like bilayers show that the binding free energy between TSP1 and CRT was reduced in apoptotic raft-like bilayer environment. This study provides molecular and structural insight into the effect of an apoptotic raft-like bilayer on the conformation and dynamics of CRT, which could enrich our understanding of CRT-mediated apoptotic-cell clearance and focal adhesion disassembly.