Carbon monoxide (CO) is an active intermediate in the cycling of carbon compounds in the atmosphere and affects the atmosphere’s oxidation capacity through its own and related reactions. Global monitoring of CO mole fractions has been extensively carried out by the National Oceanic and Atmospheric Administration (NOAA) Global Monitoring Laboratory (GML) since the 1990s. The sources and sinks of CO can be partially distinguished with isotope measurements, but observations of the CO isotopic composition are sparse. A network of independent global observatories measured 𝛿¹³C_CO and 𝛿¹⁸O_CO between 1995–2001, but the only continuous monitoring until now has been performed at Baring Head, New Zealand. As part of the Iron Salt Aerosol Methane Oxidation (ISAMO) project, regular measurements of 𝛿¹³C_CO and 𝛿¹⁸O_CO have resumed at seven stations, three of which (ZEP, IZO, RPB) overlap with the older network. In this study, we use the new and existing CO mole fraction and isotope data together with model simulations to derive empirical constraints for changes to the global and regional CO budget over the past three decades. We find a strong reduction in wintertime CO at mid-to-high latitudes in the Northern Hemisphere and relatively stable CO mole fractions across the entire Southern Hemisphere. We validate the trend of increasing CH₄ in the atmosphere concurrent with decreasing CO emissions from fossil fuel combustion, though our findings suggest that reductions in fossil fuel CO emissions in the Northern Hemisphere may be underestimated. This trend, coupled with increasing summer wildfire activity in the Northern Hemisphere, is substantially changing our understanding of CO, 𝛿¹³C_CO, and 𝛿¹⁸O_CO seasonality.