The development of non-enzymatic sensors is a challenge which requires, on the one hand, careful design of the sensing materials with respect to the chosen analyte, and on the other hand, suitable device architectures. In this work, we propose single-layer molybdenum disulfide (MoS 2) decorated with sub-nanometer Pt clusters as the sensing platform for the detection of cortisol. The aim is to assess the suitability of such a sensing platform for the development of wearable and portable cortisol sensors. For this study, we performed multi-scale computer simulations at the materials level up to device scale. First, ab initio simulations within the framework of density functional theory (DFT) allowed us to gain insights into the interaction, at the atomic level, between the analyte (cortisol) and the sensing platform (MoS 2 /Pt). Then, by carrying out technology computer-aided design (TCAD) simulations, we were able to consider a device architecture and investigate its performance as cortisol sensor. Following our multi-scale simulation strategy, we were able to assess the proposed field-effect transistor (FET) sensor, whose channel is made of Pt-decorated MoS 2. The sensing mechanism relies on the chemiresistive response of the device to the adsorption of cortisol on the channel, which leads to a charge transfer from the analyte to the substrate and, consequently, to the measurable shift in the gate voltage threshold of the FET. Our findings suggest that both the choice of the sensing materials and the proposed FET architecture are suitable for detecting cortisol by non-enzymatic means, as we predict a maximum theoretical gate voltage shift of 780 mV in ideal conditions. We may expect our results to provide the necessary basis to develop highly sensitive non-enzymatic cortisol sensors based on 2D materials decorated with Pt nanoclusters.