Membrane separation technology is an energy-efficient and green separation technology for purifying and concentrating active pharmaceutical ingredients (APIs) from organic solvents during the synthesis process. However, the lack of highly permeable materials with high rejection performance toward target molecules impedes the worldwide application of the membrane separation technology to reduce the cost of the separation process on a large scale. In the current study, we develop highly permeable thin-film nanocomposite (TFN) membranes through incorporating poly(sodium methacrylate) (SPA)-grafted UiO-66 into the polypyrrole selective layer, clarifying the effects of preparation conditions on the performance of the TFN membranes and optimizing the operation conditions on the separation performance of the TFN membranes. With finely tailored membrane structure and affinity between the TFN membranes and the solvents, the optimized TFN membranes demonstrate solution permeance as high as 88.8 L m −2 h −1 bar −1 with a rejection of about 99.9% toward octreotide acetate, exhibiting excellent rejection performance toward polypeptides and antibiotics. In the continuous operation mode, the TFN membranes still demonstrate stable permeance as high as 56.5 L m −2 h −1 bar −1 , which is about 1 order of magnitude higher than that of commercial polyamide membranes, showing strong potential in purifying and concentrating APIs from organic solvents.