Hydrogeological numerical models are essential for assessing radioactive waste disposal by understanding groundwater flow systems. These models typically rely on hydraulic head data, with other state variables often underutilized in model inversions. In Flanders' Neogene aquifer, where safety studies for Boom Clay are ongoing, existing models face uncertainties due to dependence on hydraulic heads alone. This study aims to: i) develop a conceptual model of radiogenic Helium-4 (4Herad) production and transport to reproduce observed concentrations; ii) evaluate the usefulness of 4Herad observations as an additional state variable for inverse conditioning; and iii) assess how including 4Herad affects model calibration and uncertainty reduction. We address these objectives by incorporating radiogenic Helium-4 (4Herad) as an unconventional state variable in model inversion to tackle parameter non-uniqueness. Utilizing a Bayesian approach, we employ two 3D models: a groundwater flow (GWF) model conditioned by hydraulic heads and a coupled GWF model with 4Herad production and transport, conditioned by both hydraulic heads and 4Herad concentrations. We hypothesize that integrating 4Herad will improve model accuracy and reduce uncertainties compared to using hydraulic head data alone. Findings indicate that major 4Herad sources include crustal fluxes (~57 %) and in situ Boom Clay production (~25 %). The coupled inference narrows the posterior distributions of parameters, especially for hydraulic conductivity (e.g., Mol, Diest, Berchem formations, and the Rauw Fault) and recharge, showing that 4Herad observations effectively reduce uncertainty beyond hydraulic head data. Including 4Herad improves model reliability and prediction accuracy, highlighting its importance for refining groundwater flow parameters and derived fluxes. To the best of our knowledge, this study marks the first-ever attempt at harnessing 4Herad quantitative insights into flow and transport parameters following a Bayesian approach at a catchment scale, setting a precedent for future research and emphasizing the innovative nature of this work. This study showcases a state-of-the-art approach in hydrogeological modelling, demonstrating the effectiveness of integrating 4Herad with hydraulic head observations to produce more reliable model predictions. By reducing uncertainties in crucial groundwater fluxes, this approach offers significant potential for improving geological disposal safety studies. This pioneering work advocates for the continued use of 4Herad in hydrogeological modelling, emphasizing its innovative contribution to future research and safety studies. Plain language summaryUnderstanding how groundwater flows is crucial for safely storing radioactive waste. Traditionally, models used to study groundwater rely mostly on measurements of water pressure, while other valuable data often go unused. In the Neogene aquifer in Flanders, where researchers are studying the Boom Clay formation for potential waste storage, relying only on water pressure has created uncertainties in the models. This study explores a new approach by using a different type of measurement: radiogenic Helium-4 (4Herad). The goals of the study are threefold: first, to build a model that accurately represents how 4Herad is produced and moves through the groundwater; second, to test whether including 4Herad as an additional measurement improves the model compared to using only water pressure data; and third, to see how using 4Herad affects the accuracy and reliability of the model. The study uses two types of models: one that relies only on water pressure data and another that includes both water pressure and 4Herad measurements. The idea is that 4Herad could provide additional insights and help reduce uncertainties in the model. The findings show that 4Herad comes mainly from two sources: the surrounding crust and the Boom Clay itself. Including 4Herad in the model helps narrow down uncertainties, particularly regarding how water moves through different layers and how much water is being replenished. This research is the first to use 4Herad in this way, using a formal statistical method to improve groundwater models. The results suggest that 4Herad is a valuable addition for making more accurate predictions and improving safety assessments for radioactive waste storage.