Achieving a synergistic improvement in the strength and ductility of metallic materials has long been a central challenge in materials science. Dislocation mobility limits both properties, making it difficult to strike a balance between them. The advent of multi-principal element alloys (also known as high-entropy alloys) offers a promising solution to this issue. Compared with conventional solid solution strengthened alloys, multi-principal element alloys exhibit greater lattice distortion. Consequently, dislocation movement must overcome higher and more frequent energy fluctuations, which consumes more energy. This increase in flow stress with increasing strain allows certain alloys to achieve enhanced work hardening capacity, leading to simultaneous improvements in both strength and ductility. However, two critical scientific questions in this area warrant further investigation: (1) Are multi-principal element alloys purely ideal random mixed structures, or is standardizing their local or multi-level microstructures necessary to achieve optimal performance? (2) How can we effectively standardize and regulate the microstructures of multi-principal element alloys? This study addresses these questions by proposing the concept of using negative mixing enthalpy (negative-enthalpy) alloying to standardize and regulate the microstructure of multi-principal element alloys. This study systematically explores how negative-enthalpy alloying can synergistically enhance strength and ductility while revealing new mechanisms of strengthening and toughening. Negative-enthalpy alloying affects the microstructure of metallic materials through three main effects: bond energy and slow diffusion, local chemical ordering, and interface and size effects. This approach provides a novel framework for designing and processing the microstructures of high-strength, high-ductility metallic materials at the atomic scale.