Regional, ecosystem-level conservation projects with significant vegetation management components require planning, coordination, and responsive management strategies to minimize negative impacts and maximize ecological benefits over time. The California State Coastal Conservancy’s Invasive Spartina Project (ISP) offers an example of a complex, ecosystem-scale weed eradication effort guided by regional conservation goals. We review the management framework developed by the ISP, describe decision thresholds used for site-specific management transitions over the project’s 15 years, and present strategies being used to address major challenges to project completion. These strategies include developing genetics and weed mapping approaches to aid with identification of hybrids between the introduced Spartina alterniflora and the native Spartina foliosa. The ISP also developed a tidal marsh restoration project to enhance habitat for an endangered bird, the California Ridgway’s rail (Rallus obsoletus obsoletus), that uses tall, dense forms of hybrid Spartina as high tide refugia and nesting substrate. By 2014, the ISP had installed over 300,000 native plants and recorded a greater than 96 % estuary-wide reduction in hybrid Spartina (from 323 ha to 12 net ha) despite treatment restrictions imposed at 11 sites since 2011 to protect the rail. Approximately 80 % of the remaining hybrid Spartina occurs in areas currently restricted from treatment, delaying project completion. The successes and setbacks of the ISP illustrate the complexities of achieving ecosystem-level conservation goals dependent on large-scale vegetation management.