This study proposes a practical optimal design method (PODM) for high-rise multi-outrigger structures subjected to inter-story drift constraints based on the optimality criteria method. The problem is solved through two-step calculations, which avoids time-consuming iterations owing to internal-force redistribution caused by member-section modifications, multiple inter-story drift constraints and multiple outriggers. Three parameters, namely the target virtual strain energy density (VSED), section-correction factor, and structural magnification factor, are established to relate the member-section sizes to the structural inter-story drift. The influence of internal-force redistribution is considered by adjusting the target VSED and section-correction factor based on the first trial calculation results to ensure precision. The multiple local inter-story drift constraints are converted to the unforced inter-story drift constraint, whereas the optimal design problem of the structures with multiple outriggers is solved by transforming it into the optimal design problem of the key module with the strictest demand by introducing the most critical constraint criteria. Finally, the effectiveness and accuracy of the PODM are validated using a 56-story structure and 50-story seven-bay framework.