Coastal megacities deposit significant amounts of carbon (C), nitrogen (N), and pollutants into surrounding waters. In urbanized estuaries, these inputs, including wastewater discharge and surface runoff, can affect biogeochemical cycles, microbial production, and greenhouse gas (GHG) efflux. To better understand estuarine GHG production and its connection to anthropogenic drivers, we quantified carbon dioxide (CO2) and methane (CH4) surface‐water concentrations and efflux in combination with a suite of biogeochemical parameters, including anthropogenic indicators, in the Hudson River Estuary (HRE) and adjacent waters surrounding New York, NY, over a 2‐yr period. The HRE was a source of both CO2 (33 ± 3 mmol CO2 m−2 d−1) and CH4 (177 ± 22 μmol CH4 m−2 d−1) under all measured conditions. Surface‐water salinity, oxygen saturation, fecal indicator bacteria, nitrate concentrations, and temperature best explained the variance in CO2 and CH4 concentrations in multiple regression analyses, producing robust predictive power for both GHGs. Our multifaceted data set demonstrated that CH4 and CO2 surface concentrations are explained in part by enterococci concentrations, a widely used wastewater biological indicator, explicitly linking wastewater inputs to GHG surface concentrations in the HRE. The greatest CO2 and CH4 surface‐water concentrations were found in urban tributaries and embayments, primary wastewater delivery areas throughout the HRE. Estuarine tributaries and embayments have historically received less research attention than midchannel sites, but since these shallow sites may contribute to increased GHG efflux in anthropogenically impacted estuaries, further study is warranted.