The interest of the fusion community in Pd–Ag membranes has grown in the last decades due to the high value of hydrogen permeability and the possibility of continuous operation, making it a promising technology when a gaseous stream of hydrogen isotopes must be recovered and separated from other impurities. This is the case of the Tritium Conditioning System (TCS) of the European fusion power plant demonstrator, called DEMO. This paper presents an experimental and numerical activity aimed at (i) assessing the Pd–Ag permeator performance under TCS-relevant conditions, (ii) validating a numerical tool for scale-up purposes, and (iii) carrying out a preliminary design of a TCS based on Pd–Ag membranes. Experiments were performed by feeding the membrane with a He–H2gas mixture in a specific feed flow rate ranging from 85.4 to 427.2 mol h−1m−2. A satisfactory agreement between experiments and simulations was obtained over a wide range of compositions, showing a root mean squared relative error of 2.3%. The experiments also recognized the Pd–Ag permeator as a promising technology for the DEMO TCS under the identified conditions. The scale-up procedure ended with a preliminary sizing of the system, relying on multi-tube permeators with an overall number ranging between 150 and 80 membranes in lengths of 500 and 1000 mm each.