Thermoelectric efficiency of semiconducting ruthenium silicide Ru2Si3 has been systematically studied both experimentally and theoretically. Pure and Mn-doped Ru2Si3 single crystals were grown by zone melting with optical heating. Temperature dependences of the resistivity, Hall factor, Seebeck coefficient, and thermal conductivity were studied in the range of 100–900 K. For Mn-doped Ru2Si3 crystals, the Seebeck coefficient is positive in the whole temperature range under study, it reaches its maximum value of 400 μV/K at about 500 K. At room temperature, the Seebeck coefficient of these crystals is about 300 μV/K, which is twice as high as in the undoped material. The theoretical study of transport and thermoelectric properties includes the ab initio calculation of band structure, estimation of the carrier effective masses, modeling of the electron and hole mobilities in terms of classical scattering mechanisms, and calculation of the Seebeck coefficient and thermoelectric figure of merit, ZT. The results of theoretical modeling show a good qualitative and quantitative agreement with the experimental data.