High-entropy alloys (HEAs) with a single-phased face-centered-cubic structure possess excellent plasticity but generally low strength. Precipitation strengthening is one of the most promising methods to improve the strength of alloys. However, plagued by a nerve-wracking fact that strength-ductility trade-off frequently limits the improvement of alloy properties. To overcome this problem, a new Ni35(CoFe)55V5Nb5 HEA with an excellent strength and ductility synergy was developed by introducing a novel bifunctional L12-Ni3Nb nano-precipitate. This HEA exhibits a high yield strength of 855 MPa, ultimate tensile strength of 1,302 MPa and marvelous elongation of ∼ 50%. First-principles calculations show that the (Ni24Co18Fe6)3(Nb10V4Fe2) nano-precipitate with a L12 structure possesses lower formation energy than that with D022 structure. The novel nano-precipitates provide two-fold functions. On the one hand, L12-(Ni24Co18Fe6)3(Nb10V4Fe2) nano-precipitates have a high anti-phase boundary energy, contributing to a significant increment in the yield strength through precipitation strengthening. More importantly, the precipitation of the precipitates lowers the stacking fault energy (SFE) of the alloy matrix, contributing to the excellent work-hardening ability and large plasticity through activating the continuous formation of SF networks and Lomer-Cottrell locks during deformation. The strategy to introduce the novel bifunctional nano-precipitates paves a new way to enhance the strength-ductility synergy of alloys.