While reverse osmosis (RO) is the leading technology to address the challenge of water scarcity through desalination and potable reuse of wastewater, current RO membranes still fall short in rejecting certain harmful constituents from seawater (e.g., boron) and wastewater (e.g., N-nitrosodimethylamine, or NDMA). In this study, we develop an ultra-selective polyamide (PA) membrane via enhancing interfacial polymerization using amphiphilic metal-organic framework (MOF) nanoflakes. In this process, MOF nanoflakes horizontally aligned at the water/hexane interface to accelerate the transport of diamine monomers across the interface and conserve gas bubbles and heat of reaction near the interface. These mechanisms synergistically led to the formation of a crumpled PA nanofilm with an ultrathin intrinsic thickness of ~ 5 nm and a high cross-linking degree of ~ 97%. The resulting PA membrane delivered excellent desalination performance that is beyond the existing upper-bound of perm-selectivity, and exhibited very high rejection (> 90%) of boron and NDMA unmatched by state-of-the-art RO membranes.