Context <p>The CoCrFeMnNi high-entropy alloy is renowned for its exceptional fracture toughness at cryogenic temperatures, which originates from its stable face-centered cubic structure and pronounced deformation twinning. However, for room-temperature structural applications, achieving an optimal combination of high strength and good ductility in its nanocrystalline form remains a challenge. This is partly due to the prevailing deformation mechanisms at the nanoscale, where the classical Hall–Petch strengthening can be compromised, leading to strength softening at extremely fine grain sizes. In this context, the introduction of pre-existing twins has emerged as a promising microstructural design strategy to potentially overcome this limitation and synergistically enhance both strength and plasticity. This study aims to clarify how pre-existing twins regulate the grain-size-deformation mechanism-strength-plasticity synergy in nanocrystalline CoCrFeMnNi. We systematically investigated the phase structure evolution, dislocation behavior, and strain transfer at key tensile stages (yield, initial flow, mid-flow) for grain sizes ranging from 8.110 to 13.867 nm. The results demonstrate that pre-existing twins with a &lt; 111 &gt; orientation and 5-nm spacing shift the optimal grain size for strength-plasticity synergy from 11.696 nm (untwinned) to 10 nm via a hierarchical “grain-size coupling – deformation mechanism reconstruction – strain synergistic transfer” regulation. Twin boundaries act as “obstacle-guide” features, strengthening the matrix. The 10-nm-grained alloy maintains high FCC matrix integrity, uniform HCP phase banding, and homogeneous strain transfer, achieving a yield strength of 4.36 GPa and a flow stress of 4.21 GPa. Coarser and ultra-fine grains exhibit strain concentration or disorder, disrupting synergy. This work elucidates the regulatory mechanism of pre-existing twins on the Hall–Petch relationship and critical grain size, providing a microstructural design strategy for strengthening nanocrystalline high-entropy alloys.</p> Methods <p>Atomic-scale molecular dynamics simulations were performed using the Large-scale atomic/molecular massively parallel simulator (LAMMPS). Atomic interactions were modeled using a modified embedded atom method (MEAM) potential for the Co-Cr-Fe-Mn-Ni system. Pre-existing twins with a &lt; 111 &gt; orientation and a uniform lamellar spacing of 5 nm were introduced into nanocrystalline models with average grain sizes of 8.110, 9.283, 10, 11.696, 12.599, and 13.867 nm. The total number of atoms in each model is approximately 658,080. Uniaxial tensile deformation was simulated at a constant strain rate of 1 × 10⁹ s⁻¹ at 300 K under periodic boundary conditions. Microstructural evolution was characterized using common neighbor analysis (CNA) and dislocation analysis (DXA) as implemented in the Open Visualization Tool (OVITO). The local atomic strain was calculated using the Atomic Strain analysis feature in OVITO to quantify strain transfer and localization. All visualization and quantitative data analysis were conducted with OVITO and in-house Python scripts.</p>