Background/Objectives The lipid solubility of antiepileptic drugs directly affects central nervous system availability. In relation to this, the interactions of gabapentin and levetiracetam with dipalmitoylphosphatidylcholine lipids depending on concentrations were comparatively investigated in the present study. Methods The effects of gabapentin and levetricetam as a function of concentration (1–5–10–20 mol%) on biophysical parameters of dipalmitoylphosphatidylcholine multilammelar vesicles were studied by differential scanning calorimetry and fourier transform infrared spectroscopy. Results The data revealed that gabapentin at all concentrations and levetiracetam at 1–5 mol% lowered main transition temperature, enthalpy, cooperativity, lipid fluidity, lipid order, and increased hydrogen binding capacity of glycerol and phosphate groups. However, 10–20 mol% of levetiracetam tend to show different effect on transition temperature, which could also reflect its opposing effect on lipid order and glycerol and phosphate group’s hydrations. Conclusions According to the corresponding findings depending on concentrations both drugs incorporate into phosphatidylcholines, perturbing the packing of lipids and affecting their thermotropic properties. Their binding affinity to acyl chains and hydrophilic parts of lipids was found to highly correlate with lipid-water partition and their solubility degree in water. Hence, the obtained results may offer evaluation of partition profile of the drugs into biological membranes depending on concentration.