Quantum well (QW) is one of the proposals to improve the thermoelectric properties. However, previous studies have shown that the large electron and phonon tunneling across the layers in semiconductor-based QWs and oxide-based QWs, respectively, are the two main challenges that need to be addressed. In this work, PbSe/amorphous-SrTiO3 (α-STO) supperlattices with a multiple quantum-well (MQW) structure can overcome both limitations. We demonstrate that the PbSe/α-STO MQW shows a high power factor of ∼ 24.5 μW cm−1K−2 at room temperature due to the strong quantum confine effect. In addition, the amorphous-SrTiO3 layer can engender intrinsically low thermal conductivity (0.27± 0.05 W m−1 K−1). The maximum estimated zT value is 2.7 for PbSe/α-STO MQW at room temperature, which is more than 1800 % higher than that of pure PbSe films (zT = 0.15).