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A simulation-based cycle time-throughput curve requires a large amount of simulation output data, and an experimentation framework is needed to enhance the precision and accuracy of a simulation-based cycle time-throughput curve. In this research, approaches and solutions are presented on three prime issues: 1) the establishment of the simulation sampling strategies; 2) the determination of the simulation sequences; and 3) the determination of the length of a simulation run. First, strategic simulation sampling guidelines are proposed as to how to use a fixed amount of samples when trying to generate a precise and accurate cycle time-throughput curve for complex systems. Second, in order to provide good references for the sequential experiments to generate precise simulation-based cycle time-throughput curves, a set of discrete design points is ranked sequentially. Third, a sequential stopping rule is developed to determine the length of a simulation run based on a time series forecasting procedure.