This research considers the applicability of different vegetation indices at 30 m resolution for mapping and monitoring desert wetland (cienega) health and spatial extent through time at Cienega Creek in southeastern Arizona, USA. Multiple stressors including the risk of decadal-scale drought, the effects of current and predicted global warming, and continued anthropogenic pressures threaten aquatic habitats in the southwest and cienegas are recognized as important sites for conservation and restoration efforts. However, cienegas present a challenge to satellite-imagery based analysis due to their small size and mixed surface cover of open water, exposed soils, and vegetation. We created time series of five well-known vegetation indices using annual Landsat Thematic Mapper (TM) images retrieved during the April–June dry season, from 1984 to 2011 to map landscape-level distribution of wetlands and monitor the temporal dynamics of individual sites. Indices included the Normalized Difference Vegetation Index (NDVI), the Soil-Adjusted Vegetation Index (SAVI), the Normalized Difference Water Index (NDWI), and the Normalized Difference Infrared Index (NDII). One topographic index, the Topographic Wetness Index (TWI), was analyzed to examine the utility of topography in mapping distribution of cienegas. Our results indicate that the NDII, calculated using Landsat TM band 5, outperforms the other indices at differentiating cienegas from riparian and upland sites, and was the best means to analyze change. As such, it offers a critical baseline for future studies that seek to extend the analysis of cienegas to other regions and time scales, and has broader applicability to the remote sensing of wetland features in arid landscapes.