In present work, a novel γ′′-strengthened Nb-alloyed medium-entropy alloy (MEA) was successfully fabricated and systematically investigated. Our results evidence that the γ′′ phase brings out significant precipitation hardening effect (∼10.2 %volume fraction contributes ∼ 685 MPa strength enhancement). The metastable γ′′ phase could abnormally transform to ε phase, and the morphology and distribution of ε phase shows great impacts on mechanical properties. A hetero-lamellae grain coupling with dual-precipitation (HLG + dual-P) structure was successfully constructed in this Nb-alloyed MEA, which could effectively combine precipitation hardening and hetero-deformation induced (HDI) hardening effects. Deformation characters investigations reveals that the absence of mechanical twinning in γ′′-strengthened MEA originates from the improved critical twinning stress related to the fine dislocation source size and the difficulty of high-energy complex SFs reordering. The combination of massive stacking-faults, Lomer-Cottrell locks and dynamically reinforced HDI hardening contribute to the excellent ductility and work-hardening capacity at high-level strength in the HLG + dual-P structural alloy. Our work provides a useful insight and helpful guidance for developing high-performance precipitation-hardened multi-principal element alloys.