This study presents a systematic investigation of the synergistic effect of deuterium and helium on the microstructural evolution of W–Y2O3 material during plasma exposure. The effect of single D/He and sequential D/He, He/D plasma exposure on the stability of Y2O3 nanoparticles and the microstructural evolution of the W matrix were investigated using scanning electron microscopy and transmission electron microscopy. The results indicate that Y2O3 particles undergo a significant size change during plasma exposure, and this process was significantly influenced by the synergistic effects of hydrogen and helium. The size evolution of Y2O3 particles is controlled by three mechanisms: the etching-controlled process at the initial stage, followed by deposition-controlled process or mixed-controlled processes. Interestingly, the fuzz structure on the surface of Y2O3 particles is proved to be W instead of Y2O3, which results from the deposition during plasma exposure. Significant synergistic effects of deuterium and helium were observed, in which the strong combination of H and He-vacancy composites suppressed the bubble formation and growth, leading to a different evolutionary dynamic.