The experimental lipophilicity of fumaric acid (FA) and maleic acid (MA) using the traditional shake-flask method in an n-octanol−water system using reversed-phase thin-layer chromatography (RP-TLC) was determined. Experimental partition coefficients (logPexp) were equal to −0.65 and 0.63 for MA and FA, respectively. The chromatographic lipophilicity (RMW) of the FA and MA was evaluated using reversed-phase thin-layer chromatography on RP8F254s, RP18WF254, and CNF254s plates with a mixture of an organic solvent (methanol or dioxane) and water as the mobile phase. All applied chromatographic conditions were appropriate to determine the lipophilicity of the tested MA and FA. Topological indices derived from distance matrices allowed for the development of a new method for the evaluation of the lipophilicity of MA and FA. All methods applied in this work indicate that MA is less lipophilic than FA. The methods used in this work to determine lipophilicity are of particular importance in the aspect of studying cis- and trans-configuration compounds, because generally available computer programs based on various algorithms (Virtual Computational Chemistry Laboratory and Molinspiration Cheminformatics) indicate that fumaric acid and maleic acid have identical logP values.