The microstructure significantly influences the mechanical properties of metals and alloys. Herein, we present a novel approach to tailoring the mechanical properties of a CoCrNi medium-entropy alloy by controlling nanotwin-HCP lamellae and annealing twins. It has been observed that the dislocations, three-dimensional nanotwins and Lomer-Cottrell locks, induced by equal channel angular pressing, synergistically strengthened the CoCrNi alloy. The nanotwin-HCP composite lamellae, induced by post-deformation annealing at 500 °C, resulted in high strength of 1.5 GPa and a strain of 4.1%. A superior combination of high strength (~ 1 GPa) and excellent ductility (~ 45%) has been obtained by further decorating the microstructure through producing annealing twins in recrystallized micro-sized grains. The present study presents the strengthening mechanisms and provides a generic approach to obtain the desirable mechanical properties of the alloys via microstructural optimization.