International efforts to restore degraded ecosystems will continue to expand over the coming decades, yet the factors contributing to the effectiveness of long-term restoration across large areas remain largely unexplored. At large scales, outcomes are more complex and synergistic than the additive impacts of individual restoration projects. Here, we propose a cumulative-effects conceptual framework to inform restoration design and implementation and to comprehensively measure ecological outcomes. To evaluate and illustrate this approach, we reviewed long-term restoration in several large coastal and riverine areas across the US: the greater Florida Everglades; Gulf of Mexico coast; lower Columbia River and estuary; Puget Sound; San Francisco Bay and Sacramento-San Joaquin Delta; Missouri River; and northeastern coastal states. Evidence supported eight modes of cumulative effects of interacting restoration projects, which improved outcomes for species and ecosystems at landscape and regional scales. We conclude that cumulative effects, usually measured for ecosystem degradation, are also measurable for ecosystem restoration. The consideration of evidence-based cumulative effects will help managers of large-scale restoration capitalize on positive feedback and reduce countervailing effects.