River‐dominated continental shelf environments are active sites of air‐sea CO2 exchange. We conducted 13 cruises in the northern Gulf of Mexico, a region strongly influenced by fresh water and nutrients delivered from the Mississippi and Atchafalaya River system. The sea surface partial pressure of carbon dioxide (pCO2) was measured, and the air‐sea CO2 flux was calculated. Results show that CO2 exchange exhibited a distinct seasonality: the study area was a net sink of atmospheric CO2 during spring and early summer, and it was neutral or a weak source of CO2 to the atmosphere during midsummer, fall, and winter. Along the salinity gradient, across the shelf, the sea surface shifted from a source of CO2 in low‐salinity zones (0≤S<17) to a strong CO2 sink in the middle‐to‐high‐salinity zones (17≤S<33), and finally was a near‐neutral state in the high‐salinity areas (33≤S<35) and in the open gulf (S≥35). High pCO2 values were only observed in narrow regions near freshwater sources, and the distribution of undersaturated pCO2 generally reflected the influence of freshwater inputs along the shelf. Systematic analyses of pCO2 variation demonstrated the importance of riverine nitrogen export; that is, riverine nitrogen‐enhanced biological removal, along with mixing processes, dominated pCO2 variation along the salinity gradient. In addition, extreme or unusual weather events were observed to alter the alongshore pCO2 distribution and to affect regional air‐sea CO2 flux estimates. Overall, the study region acted as a net CO2 sink of 0.96 ± 3.7 mol m−2 yr−1 (1.15 ± 4.4 Tg C yr−1).