We quantified relationships between local wetland cover in the riparian lake buffer and lake total phosphorus (TP) and water color (color) using multilevel mixed-effects models that also incorporate landscape features such as hydrogeomorphology and land use at broad regional scales to determine 1) Within regions, are local wetland relationships with TP and color affected by interactions with local land use or hydrogeomorphic variables? 2) Across regions, are local wetland relationships with TP and color different? And if so, 3) Are differences in local wetland relationships with TP and color a result of cross-scale interactions? We answered these questions by analyzing TP, color, and multi-scaled landscape data for 1790 North temperate lakes. We found that local wetland-TP and wetland-color relationships were not affected by local-scale interactions; we found that local wetland-TP and wetland-color relationships were different across regions; and these differences were related to cross-scale interactions with regional landscape characteristics. For example, regional human land-use affected local wetland-TP relationships such that in regions with high amounts of agriculture, local wetlands were associated with decreased lake TP. However, in regions with low amounts of agriculture, local wetlands were associated with increased lake TP. In contrast, regional hydrogeomorphic characteristics influenced local wetland-color relationships such that in regions with high groundwater contribution, the strength of local wetland relationships were weak. Regional landscape setting influences local wetland relationships with TP and color through cross-scale interactions and lake TP and color are controlled by both local-scale wetland extent and regional-scale landscape variables.