In the 20th century, Pendleton Island (PI) in the Clinch River of southwestern Virginia was a singularly important location for conservation of freshwater mussels in North America, supporting at least 45 species. Comprising 55,500 m² of available habitat, PI is the largest contiguous patch of habitat for mussels in the unregulated reaches of the Clinch River in either Virginia or Tennessee. Mussel density at PI declined by 96% from its historical baseline of 25/m² in 1979 to ∼1/m² in 2014, indicating a collapse of the fauna. We provide a quantitative description of the PI mussel assemblage collapse and establish baseline conditions for restoration scenarios. We examined long-term monitoring data collected at 15 sites in the Tennessee and Virginia sections of the river over a 35-yr period (1979–2014). While the mussel assemblage of PI has declined precipitously, density in the Tennessee section of the river has increased at an annual rate of 2.3% (1979–2004) and 1.3% (2004–14), stabilizing at a mean density of 29/m² over the last 10-yr period, a reasonable baseline density to gauge recovery and restoration at PI and at other disturbed sites in the river. Lost mussel abundance can and should be translated to ecosystem services loss at PI, representing more than 1.38 million mussels and tens of millions of lost mussel service years. When density of the PI mussel assemblage is projected forward 30 yr (2014–44), it returns to a baseline of 25/m² in 2036 only under a high-growth-rate scenario of 15% per yr. If realistic growth rate scenarios of 1% and 5% are used, density reaches 1.4/m² (∼75,000 individuals) and 4.3/m² (∼240,000 individuals), respectively, by 2044. These scenarios assume healthy nondegraded habitat conditions, which do not reflect current water and sediment quality at PI. Recovery of the assemblage to baseline densities will take decades and require active restoration of the fauna and habitat, including mussel translocations and stocking of hatchery-propagated juveniles.