Low carrier concentration and mobility have been the primary obstructions to improving the electrical transport properties of BiCuSeO thermoelectric oxides, particularly for excessively low carrier mobility, heavily impeding the development of its thermoelectric performance. Herein, high-pressure technology is adopted to tune the electronic structure motivating carrier mobility, incorporated with the contribution of Cu deficiency to carrier concentration, achieving high carrier mobility of 25 cm2V−1s−1 and outstanding electrical conductivity of 2834.57 Sm−1. Moreover, high densities of grain boundaries and dislocations are introduced by high pressure, accompanied by the effect of Cu vacancies, suppressing phonon transport and depressing lattice thermal conductivity, finally realizing an acceptable zT of 0.56 at 823 K in BiCu0.97SeO. This work demonstrates that high pressure can be compatible with other methods, realizing synergetic optimizations in coupled parameters and thus improving thermoelectric performance in BiCuSeO oxides.