<p>Helium is generally known as an inert element due to its high ionization potential, zero electron affinity, and low polarizability. Here, we demonstrate that Cu(I) sites with favorably coordinated ligands reach unexpectedly large He binding energies, up to 19 kJ mol^-1, due to He polarization and charge accumulation along the Cu-He bond. First, we perform accurate electronic structure calculations on a series of Cu(I)-He gas phase clusters to elucidate the nature of the Cu-He interaction. Then, we establish a predictive model to study larger systems hosting Cu(I) sites, including crown ethers, zeolites and metal-organic frameworks (MOFs). The strong Cu(I)-He interaction induces significant differences in the ⁴He/³He zero-point energies, allowing prediction of selective isotope adsorption at technologically relevant temperatures (20–77 K). In particular, undercoordinated Cu(I) sites found in zeolites and MOFs emerge as promising materials with a predicted ⁴He/³He separation factor approaching three at 20 K.</p>