Significance Salmonella causes many different diseases including gastroenteritis and typhoid fever. For infection to take place, Salmonella must enter the epithelium in the gut by injecting a number of effector proteins that trigger dramatic actin rearrangements and membrane ruffles to engulf the pathogen. In this study we identified a myosin motor protein that translocates along actin filaments as one of the crucial host proteins that are targeted by two Salmonella effector proteins, SopE and SopB, at the onset of infection. SopE and SopB exploit MYO6 to facilitate membrane ruffle formation and phospholipid production at the invasion site to mediate pathogen uptake. Myosin motors are highly druggable targets, and therefore myosin inhibitors are attractive new tools to fight bacterial infections.