ZnAl-layered double hydrcodde/H3PMo12O40 (ZnAl-LDH/PMo12) nano-hybrids were prepared by self-assembly between positively charged LDH nano-sheets and negatively charged PMo12 nano-clusters. The catalytic performance of ZnAl-LDH/PMo12 (ZAM) nano-hybrids on methyl orange (MO) degradation under room temperature and ambient pressure was investigated. The self-assembly process was evidenced by various characterization results, including X-ray diffraction, scanning electron microscopy, transmission electron microscopy, N-2 adsorption measurements, and X-ray photoelectron spectroscopy, which also suggested that the structure and morphology of the ZnAl-LDH/PMo12 hybrids played a critical role in their catalytic performance. The ZAM nano hybrid with a 1:1.59 M ratio of ZnAl-LDH to PMo12 exhibited an excellent catalytic activity for MO degradation, with a 74.2% discoloration rate and a 66.2% total organic carbon (TOC) removal efficiency. After five cycles of reactions, the discoloration rate remained at 62.5%. This high catalytic activity might be attributed to the formation of O-2(center dot-), which was generated from the reduction of the dissolved oxygen by PMo12. Overall, the results show that the formation of novel nano-hybrid catalysts through self-assembly of LDH nano-sheets with PMo12 nano-clusters leads to a significant improvement in the catalytic activity and stability of Mo based catalysts under room temperature and ambient pressure.