Leukocyte transendothelial migration (TEM) is absolutely fundamental to the inflammatory response, involving initial pseudopod protrusion and subsequent polarised migration across inflamed endothelium. Ezrin/radixin/moesin (ERM) proteins are expressed in leukocytes and mediate cell shape change and polarity. The spatio-temporal organisation of ERM with their targets, and their individual contribution to protrusion during TEM, has never been explored. Here we show that blocking PIP2 binding reduces C-terminal phosphorylation of moesin during monocyte TEM, and that on/off cycling of ERM activity is essential for pseudopod protrusion into the subendothelial space. Reactivation of ERM within transmigrated pseudopods establishes rebinding to targets, such as L-selectin. Knockdown of ezrin, but not moesin, severely impaired recruitment to activated endothelial monolayers under flow, suggesting a unique role in early recruitment. Ezrin binds preferentially to L-selectin at rest and in early TEM. Moesin/L-selectin interaction enriches within transmigrated pseudopods as TEM proceeds, facilitating localised ectodomain shedding. Non-cleavable L-selectin mutant binds selectively with ezrin, driving multi-pseudopodial extensions. Taken together, ezrin and moesin play mutually exclusive roles in modulating L-selectin signalling and shedding to control protrusion dynamics and polarity during monocyte TEM.