Urban areas are large sources of several air pollutants, with carbon monoxide (CO) among the largest. Yet measurement from space of their CO emissions remains elusive due to its long lifetime. Here we introduce a new method of estimating relative changes in CO emissions over megacities. A new multichannel Measurements of Pollution in the Troposphere (MOPITT) CO data product, offering improved sensitivity to the boundary layer, is used to estimate this relative change over eight megacities: Moscow, Paris, Mexico, Tehran, Baghdad, Los Angeles, Sao Paulo, and Delhi. By combining MOPITT observations with wind information from a meteorological reanalysis, changes in the CO upwind-downwind difference are used as a proxy for changes in emissions. Most locations show a clear reduction in CO emission between 2000–2003 and 2004–2008, reaching −43% over Tehran and −47% over Baghdad. There is a contrasted agreement between these results and the MACCity and Emission Database for Global Atmospheric Research v4.2 inventories.