Over the past decades, high-entropy alloys (HEAs) have been rapidly designed, developed, prepared, and tested to achieve superior performance across a multitude of applications. Computational materials science driven design techniques, including molecular dynamics, density functional theory, calculation of phase diagrams, phase-field modeling, crystal plasticity modelling, and artificial intelligence, combined with additive manufacturing and severe plastic deformation, present unprecedented opportunities to tailor microstructural features with remarkable flexibility and feasibility. This integration significantly enhances material properties. This review paper focuses on the computation-driven and processing-guided designs for structural HEAs (SHEAs), focusing on the relationship among materials, processing, microstructures, and properties. A succinct introduction to the computational design of SHEAs is first presented. Following this, we delve into the complex interplay between computational microstructures at various scales and the mechanical properties of SHEAs, revealing the underlying mechanisms. Additionally, we explore the distinctive features, advantages, and practical applications of these promising