Significance While transition metal-based catalysts promise lower-cost alternatives to traditional precious metals, their low activity and stability limit their deployment within industrial dehydrogenation. Here, we report the design and synthesis of ultrasmall nickel nanoclusters (∼1.5 nm) deposited on defect-rich BN nanosheet (Ni/BN) catalysts with excellent methanol dehydrogenation activity and selectivity. We found an idiosyncratic metal–support interaction not only plays a vital role in promoting the one-pot synthesis of ultrasmall Ni nanoclusters with high catalytic activity, helping to disperse and anchor the nanoclusters but also strongly enhancing the resistance to sintering and coking during methanol dehydrogenation. Calculated turnover frequency (TOF) is among the best compared with some other dehydrogenation catalysts reported previously.