Objectives. To describe national and city-level fatal drug overdose trends between 2005 and 2021 in Mexico. Methods. We calculated fatal overdose rates at the city level in 3-year periods from 2005 to 2021 and annually at the national level for people aged 15 to 64 years in Mexico. We calculated rate differences and rate ratios for each city between periods. Results. The national fatal overdose rate was 0.53 overdose deaths per 100 000 population and was almost twice as high in urban than in nonurban areas. The national fatal overdose rate was stable over the period 2005 to 2014 and increased monotonically to a peak in 2021. Fatal overdose rates varied across cities. Cities with the 8 highest fatal overdose rates in the period were all in states along the US-Mexico border. Conclusions. Fatal overdoses have doubled over the past 15 years in Mexico. Overdose rates are particularly high and increasing in cities close to the US-Mexico border. Public Health Implications. There is a need for enhanced overdose surveillance data and coordinated harm reduction strategies, particularly in the northern border region of Mexico. (Am J Public Health. Published online ahead of print May 9, 2024:e1-e9. https://doi.org/10.2105/AJPH.2024.307650).