The partitioning behavior of drug-like molecules into biomembranes has a crucial impact on the design and efficacy of therapeutic drugs. Thermodynamic properties connected with the interaction of molecules with membranes can be evaluated by calculating free energy profiles normal to the membrane surface. We calculated the free energy profiles of 25 drug-like molecules in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane and free energies of solvation in water and heptane using two methods: molecular dynamics (MD) simulations with the Berger lipid force field, and COSMOmic, based on a continuum conductor-like screening model for realistic solvation (COSMO-RS). The biased MD simulations (in total ~22 μs long) were relatively computationally expensive, whereas the COSMOmic approach offered a significantly less expensive alternative. Both methods provided similar results and showed that the studied amphiphilic drug-like molecules accumulate in the membrane, with the majority localized below the head group region. The MD simulations were more lipophilic and gave free energy profiles that were systematically deeper than those calculated by COSMOmic. To investigate the physical nature of the increased lipophilicity, we analyzed a water/heptane system and identified that it is most likely caused by overestimation of the attractive term of the Lennard-Jones potential in lipid tails. We concluded that COSMOmic can be successfully used for high-throughput computations of global thermodynamic properties, e.g., partition coefficients and energy barrier heights, in phosphocholine membranes. In contrast, MD is better for investigating local properties like molecular positioning and orientation in the membrane because they more accurately reflect the complex structure of lipid bilayers. MD is also useful for studies of highly complex systems, e.g., drug-membrane-protein interactions.