Anthropogenic nutrient inputs fuel eutrophication and hypoxia ([O2] < 2 mg L−1), threatening coastal and near shore environments across the globe. The world’s second largest anthropogenic coastal hypoxic zone occurs annually along the Louisiana (LA) shelf. Springtime loading of dissolved inorganic nitrogen (DIN) from the Mississippi River, combined with summertime stratification and increased water residence time on the shelf, promotes establishment of an extensive hypoxic zone that persists throughout the summer. We investigated the patterns of pelagic denitrification and methane (CH4) oxidation along the LA shelf. Microbial activity rates were determined along with concentrations of dissolved nutrients and greenhouse gases, nitrous oxide (N2O) and CH4, during summer in 2013, 2015, and 2016. We documented denitrification rates up to 1900 nmol N L−1 d−1 and CH4 oxidation rates as high as 192 nmol L−1 d−1 in hypoxic waters characterized by high concentrations of N2O (range: 1 to 102 nM) and CH4 (range: 3 to 641 nM). Ecosystem scaling estimates suggest that pelagic denitrification could remove between 0.1 and 47% of the DIN input from the Mississippi River, whereas CH4 oxidation does not function as an effective removal process with CH4 escaping to the atmosphere. Denitrification and CH4 oxidizing bacteria within the LA shelf hypoxic zone were largely unable to keep up with the DIN and CH4 inputs to the water column. Rates were variable and physiochemical dynamics appeared to regulate the microbial removal capacity for both nitrate/nitrite and CH4 in this ecosystem.