At any moment in nature, organisms are likely being exposed to multiple stressors, the effects of which are difficult to separate. Often, however, environmental stressors are considered on an individual basis. In southeastern Corpus Christi Bay, TX, declines in benthic macrofaunal community abundance, biomass, diversity, species richness, and species evenness have largely been attributed to the occurrence of hypoxia, a condition of low dissolved oxygen (DO). This study proposes that multiple stressors contribute to these observed benthic macrofaunal declines in southeastern Corpus Christi Bay. Therefore, a 30-year time series of water quality data (salinity, temperature, DO, pH, phosphate, ammonium, nitrite+nitrate, sulfate) and benthic community data (abundance, biomass, species richness, species evenness) was analyzed to describe 1) water quality dynamics of the region and 2) relationships between water quality dynamics and benthic macrofaunal response. Principal component analysis indicated that a large variability in the water quality dataset (63%) could be summarized by three principal components representing a multiple stressor index, a nutrient index, and an acidification index. Seasonality was found to be confounded with the multiple stressor index but not the nutrient or acidification indexes. Spearman rank-order correlations indicated both the multiple stressor and acidification indexes were inversely related to benthic macrofaunal community abundance, biomass, and species richness. A stepwise multiple linear regression analysis on individual water quality variables specified DO, and possibly temperature, to be leading explanatory variables for predicting benthic abundance. Temperature, pH, and nitrite+nitrate were indicated as leading explanatory variables for predicting benthic biomass. Temperature was indicated to be the only leading explanatory variable for predicting species richness. Results demonstrate that multiple stressors, including high temperature, high salinity, and low DO concentrations, are collectively acting on benthic communities in southeastern Corpus Christi Bay.