Higher data rates in high speed input/output (HSIO) links demand more equalization (EQ) complexity, leading to an ever larger number of possible combinations of EQ settings. Finding the optimal set of EQ parameters through exhaustive methods is prohibitive given the time-to-market requirements. This paper presents a methodology to design a statistically sufficient set of experiments for optimizing the receiver eye diagram of a HSIO link while greatly reducing the overall testing time. Our methodology is illustrated by a 5-Gbps HSIO link comprised of a Tx, a channel (including packages, vias, PCB traces, connectors and a crosstalk aggressor) and an Rx.