We report on the high thermoelectric performance of p-type polycrystalline BiCuSeO, a layered oxyselenide composed of alternating conductive (Cu2Se2)2− and insulating (Bi2O2)2+ layers. The electrical transport properties of BiCuSeO materials can be significantly improved by substituting Bi3+ with Ca2+. The resulting materials exhibit a large positive Seebeck coefficient of ~+330 μV K−1 at 300 K, which may be due to the ‘natural superlattice’ layered structure and the moderate effective mass suggested by both electronic density of states and carrier concentration calculations. After doping with Ca, enhanced electrical conductivity coupled with a moderate Seebeck coefficient leads to a power factor of ~4.74 μW cm−1 K−2 at 923 K. Moreover, BiCuSeO shows very low thermal conductivity in the temperature range of 300 (~0.9 W m−1 K−1) to 923 K (~0.45 W m−1 K−1). Such low thermal conductivity values are most likely a result of the weak chemical bonds (Young’s modulus, E~76.5 GPa) and the strong anharmonicity of the bonding arrangement (Gruneisen parameter, γ~1.5). In addition to increasing the power factor, Ca doping reduces the thermal conductivity of the lattice, as confirmed by both experimental results and Callaway model calculations. The combination of optimized power factor and intrinsically low thermal conductivity results in a high ZT of ~0.9 at 923 K for Bi0.925Ca0.075CuSeO.