The current study has demonstrated that cation dopant segregation at matrix/oxide interface opened up a new route to refine and disperse secondary oxide particles in oxide dispersion-strengthened (ODS) alloys. Thus, a unified theory that explains the physical origins of this interfacial segregation phenomenon is needed for designing ODS alloys with excellent oxide dispersity and ensuing high performance. Here, taking W-Y2O3 system for example, we firstly assess the possible driving forces for cation dopant interfacial segregation based on the experimental observation from Sc3+-, La3+-, Ti4+-, Zr4+- and Hf4+-doped W-Y2O3 alloys. It was suggested that elastic energy, oxygen chemical potential gradient and interfacial energy reduction are three main driving forces for the cation dopant segregation at W/Y2O3 interface. Then, an analytical model was developed in this work to quantitatively calculate the contributions of these three factors to the total segregation energy. Finally, the coupled results are further validated with the density functional theory (DFT)-calculated total segregation energy, and the good consistency confirms again the underlying mechanism behind cation dopant segregation phenomenon in W-based ODS alloy. On this basis, it can be predicted that a chemically expanded lattice and a large oxygen affinity will promote dopant interfacial segregation and enable the microstructure of ODS alloys to be tailored desirably. More importantly, the results and analytical model in our work can provide theoretical guidance for choosing proper cation dopant for other ODS alloys and then enhancing their strength and ductility simultaneously. Besides, the high-temperature instability of secondary oxide particles under extreme working environment also can be solved easily using this method.