Propofol (2,6-bis(1-methylethyl)phenol) is a small lipophilic neuroactive drug used extensively in anesthesia. While its mechanism of action is known, its temporary effects on the lipid composition of cell membranes have not been fully elucidated. A structurally related series of saturated phospholipids with C14-acyl chains and different polar head groups is utilized in the present study with a view to understanding specific drug–lipid interactions in model membranes at the air–water interface. Langmuir surface pressure–area isotherms show that propofol can shift the lipid phase transitions to higher areas per lipid molecule and surface pressures. Brewster angle microscopy imaging shows that the drug exhibits a fluidizing effect on the lipid morphology, resulting in the formation of bright circular domains with reduced line tension. Neutron reflectometry reveals effects of squeezing out of the drug from the membranes during membrane compression, as the location and amount of the drug are quantified for these systems for the first time. The greatest overall drug−lipid interactions are with the phosphatidylcholine lipid, where the drug is located predominantly in the relatively fluid acyl chains. The greatest drug−lipid head group interactions are with the phosphatidylethanolamine lipid, which is discussed as an interplay between its squeezing out from the acyl chains due to their more condensed nature and possible specific interactions between the hydroxyl group on the drug and the ammonium group on the lipid head group. An absence of drug interactions was observed with the charged head group of the phosphatidylglycerol lipid. It is concluded that changes in membrane fluidity caused by different lipid polar head groups modulate the extent and nature of the drug–membrane interactions more generally than specific intermolecular interactions between chemical groups or effects of lipid head group charge. These new findings provide a fresh perspective on the processes influencing lipid interactions of a small hydrophobic drug and its distribution within lipid membranes, understanding which links to reducing side effects in patients from medication-induced changes to cell membrane composition