Advances in surgical instrumentation allow surgeons to treat patients with less morbidity and shorter recovery time. However, the increasing complexity also adds to surgical risk, and to operating room supply chain burden. To improve the quality and efficiency of operating room instrument availability, we developed and validated a Lean 5S approach consisting of sort (determining instrument usage and waste), simplify (removing unnecessary instruments), sweep (confirm availability of needed instruments), standardize (all trays the same for a given procedure), and self-discipline (monitor success). The primary outcome was reduction in unnecessary instruments delivered to the operating room. As a secondary analysis, we evaluated the effect of the Lean instrument intervention on surgery times. We reduced the number of instruments for minimally invasive spine surgery by 70% (from 197 to 58), and setup time decreased 37% (13.1-8.2 min, p = .0015). We also report subsequent validation of the approach on deep brain stimulator cases. We conclude that complex surgical procedures offer opportunities for substantial waste reduction, simplification, and quality improvement, with potential institutional annual cost savings of $2.8 million. We demonstrate that Lean methodology can improve quality at lower cost.