Passive permeation through an epithelial membrane may be enhanced by using a class of amphiphilic molecules known as permeation enhancers (PEs). PEs have been studied in clinical trials and used in coformulations with peptides and small molecule drugs, and yet, an understanding of the permeant-PE interactions leaves much to be desired. This manuscript uses all-atom molecular dynamics (MD) simulations to showcase the effects of sodium caprate (C10) and salcaprozate sodium (SNAC), two commonly applied PEs, on membrane properties and the free energy profiles of five small molecule drugs (mannitol, atenolol, ketoprofen, decanedecaol, mucic acid). Our results show that both C10 and SNAC make the lipid molecules pack more densely, but C10 increases the lipid lateral diffusivity while SNAC decreases it. The change in the lipid order parameter also shows both PEs increasing the order near the lipid heads, possibly due to the dense packing in the membrane. A decrease in the central barrier of the permeation free energy was observed by embedding PEs into a lipid bilayer and SNAC is more efficient in doing so than C10. Neither SNAC nor C10 has a large impact on the diffusion coefficient of the small molecules. The analysis of the MD simulations revealed that PEs make the membrane tail region more hydrophilic by forming hydrogen bonds with small molecule drugs, i.e., decreasing the central barrier of the permeation free energy. While this study was only limited to small molecule drugs, this lays the groundwork for future studies to which the effects of the PEs in the permeation of macromolecules and peptides may be observed.