Abstract Objective To describe and quantify the effect of quality control (QC) metrics to increase testing efficiency in a high-complexity, Clinical Laboratory Improvement Amendments–certified laboratory that uses amplicon-based, next generation sequencing for the clinical detection of SARS-CoV-2. To enable rapid scalability to several thousands of specimens per day without fully automated platforms, we developed internal QC methods to ensure high-accuracy testing. Methods We implemented procedures to increase efficiency by applying the Lean Six Sigma model into our sequencing-based COVID-19 detection. Results The application of the Lean Six Sigma model increased laboratory efficiency by reducing errors, allowing for a higher testing volume to be met with minimal staffing. Furthermore, these improvements resulted in an improved turnaround time. Conclusion Lean Six Sigma model execution has increased laboratory efficiency by decreasing critical testing errors and has prepared the laboratory for future scaling up to 50,000 tests per day.