Annealing-regulated precipitation strengthening combined with cold-working is one of the most efficient strategies for resolving the conflict between strength and ductility in metals and alloys. However, precipitation control and grain refinement are mutually contradictory due to the excellent phase stability of multicomponent alloys. This work utilizes the high-temperature extrusion and annealing to optimize the microstructures and mechanical properties of the Co34Cr32Ni27Al3.5Ti3.5 multicomponent alloy. Hot extrusion effectively reduces grain sizes and simultaneously accelerates the precipitation of coherent L12 nanoparticles inside the face-centered cubic (FCC) matrix and grain boundary precipitations (i.e., submicron Cr-rich particles and L12-Ni3(Ti, Al) precipitates), resulting in strongly reciprocal interaction between dislocation slip and hierarchical-scale precipitates. Subsequent annealing regulates grain sizes, dislocations, twins, and precipitates, further allowing to tailor mechanical properties. The high yield strength is attributed to the coupled precipitation strengthening effects from nanoscale coherent L12 particles inside grains and submicron grain boundary precipitates under the support of pre-existing dislocations. The excellent ductility results from the synergistic activation of dislocations, stacking faults, and twins during plastic deformation. The present study provides a promising approach for regulating microstructures, especially defects, and enhancing the mechanical properties of multicomponent alloys.