The interfacial tensile yield strengths of Cu/Nb layered materials containing helium bubbles are investigated via molecular dynamics simulations. Specifically, the effects of helium bubble internal pressure, bubble size, and layer thickness on the interface tensile yield strength and deformation mechanism of Cu/Nb layered materials are investigated. Results show that interface helium bubbles can induce interface dislocation nucleation, change the microstructural evolution, and significantly reduce the interface tensile yield strength of Cu/Nb layered materials. The effect of helium bubbles on the interface tensile yield strength weakens as the helium bubble size increases resulting in apparent size effect. Compared with the case without helium bubbles, the interface tensile yield strength reduced by approximately 12% and 33% for the models containing 3 and 6 nm helium bubbles, respectively. Additionally, the layer thickness minimally affects the upper yield stress of the Cu/Nb-layered materials, whereas it significantly affects the lower yield stress. The former is attributed to the structure symmetry of the Cu/Nb interface and the loading symmetry, which render the interface stress and dislocation nucleation stress insensitive to the layer thickness. The latter is due to the increased layer thickness, which provides more space for dislocation motion and evolution, thus resulting in rapid stress reduction during the yield period.