Methods for assessing wetland conditions must be established so wetlands can be monitored and ecological services can be protected. We evaluated biological indices compiled from macroinvertebrate and diatom metrics developed primarily for streams to assess their ability to indicate water quality in connected depression wetlands. We collected water-quality and biological samples at 24 connected depressions dominated by water tupelo (Nyssa aquatica) or bald cypress (Taxodium distichum) (water depths = 0.5–1.0 m). Water quality of the least-disturbed connected depressions was characteristic of swamps in the southeastern USA, which tend to have low specific conductance, nutrient concentrations, and pH. We compared 162 macroinvertebrate metrics and 123 diatom metrics with a water-quality disturbance gradient. For most metrics, we evaluated richness, % richness, abundance, and % relative abundance values. Three of the 4 macroinvertebrate metrics that were most beneficial for identifying disturbance in connected depressions decreased along the disturbance gradient even though they normally increase relative to stream disturbance. The negative relationship to disturbance of some taxa (e.g., dipterans, mollusks, and crustaceans) that are considered tolerant in streams suggests that the tolerance scale for some macroinvertebrates can differ markedly between streams and wetlands. Three of the 4 metrics chosen for the diatom index reflected published tolerances or fit the usual perception of metric response to disturbance. Both biological indices may be useful in connected depressions elsewhere in the Mississippi Alluvial Plain Ecoregion and could have application in other wetland types. Given the paradoxical relationship of some macroinvertebrate metrics to dissolved O₂ (DO), we suggest that the diatom metrics may be easier to interpret and defend for wetlands with low DO concentrations in least-disturbed conditions.