Colombia and Mexico are among the countries in the region with the highest rates of homicide mortality and are also the drug traffickers in the world. The objective of this study was to analyze the trends and differences in homicide mortality in Colombia and Mexico between 1990 and 2016. Using data from the Global Burden of Disease Study, we report mortality rates and trends in years of life lost to homicides. This study looked at injuries occurring because of interpersonal violence, which was divided into three types (firearm, sharp object, and others). The homicide mortality rate steadily decreased since 1992 in Colombia, while in Mexico, it varied over time. This rate in Colombia has not been reduced to Mexico’s level, and in turn, Mexico has not had a mortality rate as high as Colombia’s. Throughout the period, in both countries, the years of life lost rate decreased (52% in Colombia and 18.6% in Mexico); however, between 2002 and 2016, the years of life lost rate from homicides was reduced in all age groups in Colombia, and in Mexico, they increased notably, mainly between 15 and 54 years of age. Public health plays a central role in abating interpersonal violence through the prevention of risk factors, and through making information available so that decision-makers can create public policies using evidence-based arguments. The Global Burden of Disease Study is a crucial resource that can be used to define, describe, and evaluate the consequences of homicides and help direct efforts and resources to the most vulnerable groups.