N2O is a GHG of environmental concern. It is generated from the nitrous material contained in wastewater and is the sixth most important contributor to N2O emissions. There is a great variety of methods to quantify the emission of N2O in a wastewater treatment plant (WWTP), which present variants among them, such as predetermined values and operational data of the plants. In this paper, we compared three different methods to quantify the N2O emission in 2015 from WWTP in two metropolitan areas with high population density: Mexico City and the Metropolitan Area of Barcelona (MAB). MAB has advanced treatment plants that remove nutrients from wastewater, and Mexico City has only traditional treatment plants. The N2O emission/inhabitant from WWTPs in MAB (3,214,211 inhabitants served) was 40% lower than the plants in Mexico City (1,806,440 inhabitants served). The MAB emission was 0.009 tCO2e/inhabitant and 0.013 tCO2e/inhabitant in Mexico City; these emission values could be considered statistically different with a risk error of 5%. This difference could be due to the fact that MAB has nutrient removal (42% of inhabitants served), and Mexico City has only traditional treatment plants. The results obtained may be influenced by the default emission factors of each methodology. In addition, per capita protein consumption and water consumption per inhabitant are different parameters that must be considered between these zones to quantify and compare the emission of N2O. The integral methods are closer to the reality of the N2O emission when the operating parameters of each plant and wastewater are considered. There should be more research on the reduction of this GHG in wastewater treatment for a correct quantification of these emissions, and more especially in the estimation of N2O emission factors suitable for each treatment plant and study area.