Previous studies have demonstrated the potential for non-steroidal anti-inflammatory drugs (NSAIDs), in particular aspirin, to be used as chemopreventives for colorectal cancer; however, a range of unwanted gastrointestinal side effects limit their effectiveness. Due to the role of bismuth in the treatment of gastrointestinal disorders, it is hypothesized that bismuth-coordinated NSAIDs (BiNSAIDs) could be used to combat the gastrointestinal side effects of NSAIDs while still maintaining their chemopreventive potential. To further understand the biological activity of these compounds, the present study examined four NSAIDs, namely, tolfenamic acid (tolfH), aspirin (aspH), indomethacin (indoH), and mefenamic acid (mefH) and their analogous homoleptic BiNSAIDs ([Bi(L)3]n), to determine how these compounds interact with biological membrane mimics composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or a mixture of POPC and cholesterol. Electrical impedance spectroscopy studies revealed that each of the NSAIDs and BiNSAIDs influenced membrane conductance, suggesting that temporary pore formation may play a key role in the previously observed cytotoxicity of tolfH and Bi(tolf)3. Quartz crystal microbalance with dissipation monitoring showed that all the compounds were able to interact with membrane mimics composed of solely POPC or POPC/cholesterol. Finally, neutron reflectometry studies showed changes in membrane thickness and composition. The location of the compounds within the bilayer could not be determined with certainty; however, a complex interplay of interactions governs the location of small molecules, such as NSAIDs, within lipid membranes. The charged nature of the parent NSAIDs means that interactions with the polar headgroup region are most likely with larger hydrophobic sections, potentially leading to deeper penetration.