Abstract: Nanolayered metals exhibit excellent properties such as wear resistance, radiation damage resistance, and ultra-high strength, which are highly anticipated for applications in high-end equipment in aerospace, aviation, and nuclear industries. However, they suffer from the trade-off between strength and toughness, failing to meet the requirements of the high-end equipment exposed to harsh environment. Existing experiments have confirmed that constructing nanolayered metals with interlayers is an effective strategy for strengthening and toughening nanolayered metals, but the complexity and diversity of interlayer structures have kept their strengthening and toughening mechanisms unclear. In this paper, molecular dynamics simulations are employed to investigate the compressive deformations of six Cu/Ni nanolayered metals with different face-centered cubic (FCC) crystal interlayers. The stress-strain responses show the differences in strengthening effects among these metals. Based on the dislocation nucleation process, the correlation between interlayer characteristic parameters and strength is established. A suggestion for strengthening nanolayered metals with interlayers is proposed. Simulation results show that introducing Pd, Ag, Pt, Au, Pb, and Al interlayers into Cu/Ni nanolayered metals enhances their strength, with the strengthening effect decreasing in the above order. The interlayer elastic modulus plays a dominant role in governing the strength of nanolayered metals. Interlayers with low elastic modulus tend to bear additional elastic deformation, which induces a rapidly increase in atomic energy at the interface. Dislocation nucleation is facilitated by the rapid energy accumulation, which reduces the elastic strain and consequently results in reduced strength. The energy distribution of interfaces reveals that the atomic potential energy of dislocation lines is lower than that of both the coherent region and the stacking fault region of the interface. An increase in the lattice constant difference enhances the interfacial dislocation density, reduces the initial interfacial energy due to more atoms with low energy at dislocation lines. The energy required for dislocation nucleation is enhanced, resulting in a larger elastic modulus, and strengthens the models.