Efficient thermoelectric (TE) conversion of waste heat to usable energy is a holy grail promising to address major societal issues related to energy crisis and global heat management. For these to be economical, synthesis of a solid-state material with a high figure-of-merit (ZT) values is the key, with characterization methods quantifying TE and heat transport properties being indispensable for guiding the development of such materials. In the present study, a large enhancement of the TE power factor in Sb ₂Te ₃/MoS ₂ multilayer structures is reported. A new approach is used to simultaneously experimentally determine the values of in-plane (k _xy) and out-of-pane (k _z) thermal conductivities for multilayer samples with characteristic layer thickness of few nanometres, essential for the quantification of the ZT, the key parameter for the TE material. Combining simultaneous enhancement in the value of in-plane power factor (to (4.9 ± 0.4) × mWm ⁻¹ K ⁻²) and reduction of the in-plane value of the thermal conductivity (to 0.7 ± 0.1 Wm ⁻¹ K ⁻¹) for Sb ₂Te ₃/MoS ₂ multilayer sample led to high values of ZT of 2.08 ± 0.37 at room temperature. The present study, therefore, sets the foundation for a new methodology of exploiting the properties of 2D/3D interfaces for the development of novel fully viable thermoelectric materials.