The limited thermal and water stability of metal-organic frameworks (MOFs) often restricts their applications in conventional catalysis involving thermal treatment and/or use of water. Non-thermal plasma (NTP) is a promising technique that can overcome barriers in conventional catalysis. Here we report an example of NTP-activated water-gas shift reaction (WGSR) over a MOF (HKUST-1). Significantly, the exceptional stability of HKUST-1 has been sustained under NTP activation and in the presence of water, leading to a high specific rate of 8.8 h−1. We found that NTP-induced water dissociation has a two-fold promotion effect in WGSR, facilitating WGSR by supplying OH, and sustaining the stability and hence activity of HKUST-1. In situ characterisation of HKUST-1 revealed the critical role of open Cu sites in the binding of substrate molecules. This study paves the way for utilising MOFs for a wider range of catalysis.