Achieving highly selective acetylene semi‐hydrogenation in an ethylene‐rich gas stream is of great industrial importance. Herein, we construct isolated single Pd atom in a polyoxometalate‐based metal‐organic framework (POMOF). The unique internal environment allows this POMOF to separate acetylene from acetylene/ethylene gas mixtures and confine it close to the single Pd atom. After semi‐hydrogenation, the resulting ethylene is preferentially discharged from the pores, achieving a selectivity of 92.6 %. First‐principles simulations reveal that the adsorbed acetylene/ethylene molecules form hydrogen bond networks with oxygen atoms of SiW12O404− and create dynamic confinement regions, which preferentially release the produced ethylene. Besides, at the Pd site, the over‐hydrogenation of ethylene exhibits a higher reaction energy barrier than the semi‐hydrogenation of acetylene. The combined advantages of POMOF and single Pd atom provides an effective approach for the regulation of semi‐hydrogenation selectivity.