Zebra mussels (Dreissena polymorpha) are an invasive bivalve that has spread across much of the central and eastern U.S. since their initial introduction to North America. Eradication efforts have largely relied on chemical control methods, which can be costly and not always effective. In 2014, a highly localized introduction of zebra mussels was discovered in the 35.6 km2 Lake Waco in Central Texas, USA. After weighing treatment options, a decision was made to attempt eradication using a novel gas impermeable benthic barrier approach previously only used for bivalves to successfully suppress Asian clam (Corbicula fluminea) populations. A polyvinyl chloride benthic barrier was installed to cover an area of approximately 3,900 m2 of the shoreline and lake bottom in the littoral zone and left in place for nearly five months with frequent monitoring and periodic maintenance. Following barrier removal, environmental DNA, plankton sampling for larvae, and shoreline/substrate surveys for settled mussels were implemented to monitor eradication effort success. Although two live mussels were found immediately after barrier removal indicating mortality was not 100%, there were no further detections of zebra mussels suggesting an insufficient number remained posttreatment to develop a population. Following over five years with no detections, the zebra mussel population was declared to be eradicated from the lake in early 2021. This is the first demonstrated use of a benthic barrier approach to successfully eradicate a dreissenid mussel introduction. The use of this technique was facilitated by early detection, the localized nature of the introduction, cooperation in closing the boat ramp in the affected area, the gently sloping bathymetry of the lake’s littoral zone, and partnership efforts and contributions by multiple agencies and other entities. Lake Waco remains at risk for future zebra mussel re-introduction and early detection monitoring is ongoing.