A semi-automated and fully integrated millifluidic platform has been developed for rapid development and study of Solid-phase extraction (SPE) processes. In this instrumented setup, the fluid coming out of the extraction mini-column is analysed directly using on-line X-ray fluorescence, enabling a real-time, fast and accurate measurement of the elemental concentrations within the flowing liquid. This platform aims at enhancing and facilitating the development of SPEs whose numerous experimental parameters make it time consuming to optimize and upscale. Hence, this approach solves the labour intensity issue and is as accurate as off-line Inductively Coupled Plasma, for instance. This is exemplified with a system comprising of a mixture of Rare-Earth Elements (REEs) and Iron, whose separation is investigated as a function of various experimental parameters. It enabled us to study the performance of the newly released METALICAPT® commercial materials and to determine an optimized path towards the almost total separation of Iron from the initial mixture. Overall, the original SPE process reported herein demonstrates the platform’s reliability, performance and range of applicability.