Substitution of the heteroatoms in the aromatic end‐groups of three diketopyrrolopyrrole containing small molecules is investigated to evaluate how such substitutions affect various physical properties, charge transport, and the performance in bulk heterojunction solar cells. While the optical absorption and frontier orbital energy levels are insensitive to heteroatom substitution, the materials' solubility, thermal properties, film morphology, charge carrier mobility, and photovoltaic performance are altered significantly. Differences in material properties are found to arise from changes in intra‐ and intermolecular interactions in the solid state caused by heteroatom substitution, as revealed by the single crystal structures of three compounds. This study demonstrates a systematic investigation of structure–property relationships in conjugated small molecules. The effects of heteroatom substitutions on the functional properties of diketopyrrolopyrrole‐containing molecules are systematically investigated to identify the internal structure–property relationships. While the optical absorption and energy levels are insensitive to the heteroatom substitution, the materials' single crystal structures, capability of film formation, carrier mobility, and photovoltaic performance are significantly changed by the heteroatom substitutions.