Railway bogies of the Y25 family are the most common type of freight bogies used in Europe. However, this family of bogies presents poor curving performance and a derailment history. Although numerical simulations are a powerful tool to study railway dynamics, derailment scenarios involve complex operational and vehicle conditions that increase the multivariate aspect of the problem. Thus, simulating all possible scenario variants is unfeasible from the computational perspective due to time and computational constraints. This paper proposes an approach based on a Response Surface Methodology to study the combined influence of uncertain parameters on the derailment potential of a railway vehicle. The potential of this approach is demonstrated using a real derailment as a case study. A set of scenarios is identified using a Design of Experiments approach, and is simulated on a commercial software. The response functions of the quantities used to assess derailment are generated, and the conditions that maximise the derailment potential are identified. The results reveal a combination of asymmetric loading, excessive speed, and Lenoir link failure may cause extreme wheel unloading in the study developed. This work reveals the advantages of a Response Surface Methodology to identify the conditions that maximise the derailment potential.