AbstractAs a unique class of molecular electronic materials, organic donor–acceptor complexes now exhibit tantalizing prospect for heat–electricity interconversion. Over the past decades, in design of these materials for thermoelectric applications, consistent efforts have been made to synthesize a wide variety of structures and to characterize their properties. However, hitherto, one of the paramount conundrums, namely lack of systematic molecular design principles, has not been addressed yet. Here, based on ab initio calculations, and by comprehensively examining the underlying correlation among thermoelectric power factors, non-intuitive transport processes, and fundamental chemical structures for 13 prototypical organic donor–acceptor complexes, we establish a unified roadmap for rational development of these materials with increased thermoelectric response. We corroborate that the energy levels of frontier molecular orbitals in the isolated donor and acceptor molecules control the charge transfer, electronic property, charge transport, and thermoelectric performance in the solid-state complexes. Our results demonstrate that tailoring a suitable energy-level difference between donor’s highest occupied molecular orbital and acceptor’s lowest unoccupied molecular orbital holds the key to achieving an outstanding power factor. Moreover, we reveal that the charge-transfer-caused Coulomb scattering governs the charge and thermoelectric transport in organic donor–acceptor complexes.