Mixed-matrix membranes (MMMs) have been drawing increasing attention due to the high permeability and high rejection capabilities for highly efficient wastewater treatment applications. Nonetheless, improving the water permeance while maintaining the high rejection capability is still an ongoing challenge for the practically state-of-the-art MMMs. Herein, a new class of poly(ether sulfone) (PES) based MMM containing metal–organic framework (MOF) nanofillers of HKUST-1 and blending with poly(methyl methacrylate-co-methacrylic acid) (PMMA-co-MAA) copolymer, designated as HKUST-1@mPES MMM, were developed for the highly efficient ultrafiltration (UF) process. In this study, the nanosized HKUST-1 nanofillers were removed by water dissolution as sacrificial templating materials, so that the additional nanovoids were deliberately generated throughout the dense polymer matrix. The introduction of PMMA-co-MAA copolymer facilitated the even dispersion of HKUST-1 nanofillers in a polymer matrix, by constructing the bridge connection between inorganic nanofillers and organic matrix. The resultant HKUST-1@mPES MMM exhibited a high pure water permeability (PWP) up to 490 L·m^–2·h^–1·bar^–1, substantially reaching nearly 3 times higher than that of the mPES membrane without HKUST-1 nanofillers loading and maintaining a relatively high BSA rejection rate of 96% without obvious deterioration. The newly developed HKUST-1@mPES MMM thereby exhibited a comparable separation efficiency compared to the cutting-edge UF membranes reported so far. Overall, the nanovoid-generated approach provides new insight into developing advanced MMMs used for highly efficient water treatment applications.