A watershed-based assessment of wetland impacts and compensatory mitigation was conducted for the Cuyahoga River Watershed (CRW) in northeastern Ohio, USA, to explore the effectiveness of wetland mitigation regulations and any resulting cumulative changes to wetland and landscape structure. Mitigation projects from 23 Section 401 certifications and Ohio Isolated Wetland permits were evaluated for permit compliance, wetland structure, and landscape context. Although there was a net gain in wetland area as a result of the 23 permits, the CRW experienced a net loss of wetland acreage due to the exportation to mitigation banks located outside the watershed. The majority of projects (67%) that restored or created wetlands independently (not at a mitigation bank) were not successful at meeting permit requirements in terms of wetland area. The comparison of impacted and mitigation wetland vegetation types revealed an increase in open-water/emergent wetland area and a decrease in area of scrub/shrub and forested wetlands, along with a decrease in the number of wetlands from 134 impacted wetlands to 65 mitigation wetlands. Impacted wetlands were significantly smaller than replacement wetlands. Landscape composition surrounding the wetlands was highly variable, varying from 17%–75% natural land uses and from 18%–82% human land uses. We suggest that an improvement in compliance with permit requirements is necessary. Current wetland policy allows for the exportation of wetlands for mitigation purposes, which can result in the loss of wetlands from some hydrologic units. The consideration of wetland structure needs to be incorporated into the regulatory process to avoid a shift in wetland types that are present. Finally, instead of reviewing projects on a site-by-site basis, a landscape approach should be taken in order to avoid the loss of upland-wetland heterogeneity and the placement of mitigation wetlands in degraded landscapes.