To accelerate the exploration, screening, and discovery of structural high-entropy alloys with targeted properties, the newly developed High-Throughput Hot-Isostatic-Pressing based Micro-Synthesis Approach (HT-HIP-MSA) is employed to efficiently synthesize and characterize 85 combinatorial alloys in a 13-principal element alloying space. These CoCrFeNi-based high entropy alloys span 1 quaternary, 9 quinary, and 36 senary alloy systems, and their composition-structure-property relationships are characterized and analyzed experimentally and computationally. From the single-phase FCC CoCrFeNi alloy base, with Mn, Cu, Ti, Nb, Ta, Mo, W, Al, and Si as principal element alloying additions, we find (1) the extended Mn solubility in the single-phase FCC CoCrFeNi-Mn-x alloys, (2) the destabilizing behavior for most of the quinary and senary alloys, and (3) the distinctive solid-solution-strengthening effects in the alloys. In combining the computational methods, the HT-HIP-MSA can be systematic and economic to explore and refine the compositions, structures, and properties of structural high-entropy alloys. (C) 2021 Published by Elsevier Ltd on behalf of Chinese Society for Metals.