Numerous unwanted cells are removed from epithelial and endothelial tissues—in which cells are tightly connected to one another—without disturbing tissue integrity and homeostasis. Cell extrusion is a unique mode of cell removal from tissues, and it plays an important role in regulating cell numbers and the eliminating unwanted cells, such as apoptotic cells, cancer cells, and cells with a lower fitness in cell competition . During this process, cells delaminate from the cell layer, to which they initially used to adhere, through communication with the neighboring cells. Defects in cell extrusion are believed to associate with inflammation and cancer in epithelium as well as blood vessel dysfunction. However, the correlation between them has not yet been evaluated owing to a lack of knowledge of the underlying mechanisms. In particular, the process whereby the cell exit from the tissue remains to be elucidated. Here, we report a novel and conserved execution mechanism of cell extrusion—common to mammalian cells and Drosophila epithelia—i.e., spatiotemporally regulated extracellular vesicle formation in extruding cells at a site opposite to the direction of extrusion. Particularly, we found that a lipid-scramblase‒mediated local exposure of phosphatidylserine is responsible for extracellular vesicle formation and is crucial for the execution of cell extrusion, and inhibition of this process disrupted prompt cell delamination as well as tissue homeostasis. Furthermore, we revealed the mechanism underlying vesicle formation. Importantly, our results reveal that membrane dynamics is the driving force by a “rocket launch”-like mechanism behind the extrusion of cells from tissues, a fundamental cell behavior in multicellular organisms that is also observed in other contexts including cancer cell invasion and neural cell differentiation. Our understanding of this new mechanism of cell extrusion enables us to examine the relationship between cell extrusion abnormalities and the onset of various diseases.