This study attempted to optimize the compositions of microemulsion mobile phase to model the drug penetration across blood-brain barrier (BBB) by microemulsion liquid chromatography (MELC). During the study, a continuous increase of the retentions along the operation time was found for all the test drugs. A correction method using methyl paraben and propranolol as the internal standards was proposed, which improved the reliability of the retention time significantly. The corrected retention factors were then used to develop the predictive model. The optimized MELC system with microemulsion consisting of 3.3% sodium dodecyl sulfate (SDS)-6.6% butanol-1.6% heptane-88.5% phosphate buffer (pH 7.0) showed superiorities to other lipophilicity measuring systems for modeling BBB penetration.