The Salton Sea in California is an important habitat for fish and waterfowl. Its ecosystem is threatened due to diminishing water supplies and increasing salinity. An alternative source of water to support species conservation habitat may be obtained from local rivers (e.g., Alamo or New Rivers), provided that a wetland treatment system can be developed to remove selenium (Se), fertilizer nutrients, and other contaminants. Here, we used mesocosms to evaluate a number of potential design options (e.g., plant species selection, sediment composition and arrangement, forced aeration, organic amendments, etc.) to improve the efficiency of Se removal using treatment wetlands. Our results show that, of five different substrate arrangements tested for Se removal, the most efficient was obtained for cattails growing in a substrate of cattail litter overlying sand and peat moss sediment (water column Se was reduced from 15 μg Se/L to <0.1 μg Se/L in 72 h). The addition of organic amendments in the form of alfalfa hay or alfalfa meal was also helpful in lowering Se levels. These results suggest that it may be possible to design constructed wetland water treatment systems capable of reducing Se concentrations in river water to values below 1 μg Se/L.