The separation of C2H2 from CO2 is an important process for industrial achievement of gaseous precursor C2H2, which is yet challenged by the well-known trade-off between capacity and selectivity derived from their close physical properties (such as the nearly identical kinetic molecular sizes). Herein, we experimentally screen a series of Hoffman-type metal organic frameworks (MOFs) and regulate the pore size and functionality by introducing different metal cation and organic linkers. We find that among the obtained MOFs, a Ni2+ based MOF (termed as Ni-Pz) shows the best performance of efficient C2H2 separation from CO2, featuring both high capacity (106 cm3/g) and selectivity (10.8). Moreover, to the best of our knowledge, Ni-Pz has never been explored in C2H2 related separation before and is the only MOF that balances the adsorption capacity (>100 cm3/g), selectivity (>10), adsorption heat (<45 kJ/mol) and stability (>400 °C; pH = 1–12). Grand Canonical Monte Carlo (GCMC) simulations reproduce the experimental results and reveal several typical binding configurations of C2H2/CO2 in Ni-Pz. Density functional theory calculations corroborate that the binding configurations from GCMC are very stable and that C2H2 has stronger binding affinity inside the cavity of Ni-Pz than CO2. Practical separation performance is further demonstrated by dynamic breakthrough experiments with good recyclability. Overall, our findings highlight that the Ni-Pz MOF screened from various Hoffman-type MOFs is an excellent candidate for industrial application.