Amphiphilicity is an important property for drug development and self-assembly. This paper introduces a general approach based on a simple fatty alcohol (dodecanol) membrane model that can be used to quantify the amphiphilicity of small molecules that are in good agreement with experimental surface tension data. By applying the model to a systematic series of compounds, it was possible to elucidate the effect of different motifs on amphiphilicity. The results further indicate that amphiphilicity correlates strongly with water-octanol partition coefficients (logP) for the 29 organic molecules examined in the 0 < logP < 4 range. Importantly, the simulation of the model membrane is an order of magnitude faster than a phospholipid membrane (e.g., 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) simulation and offers a simple atomistic approach for quantifying and predicting amphiphilicity of small drug-like molecules that could be used in quantitative structure-activity relationship studies.