Background: In Mexico, homicides are the leading cause of death among men aged 15 to 44 years; however, despite their increase in recent decades, the study of this issue is insufficient, given its magnitude and impact. Therefore, this study aimed to characterize the spatial and temporal patterns and associated factors of homicides in Mexico from 2015 to 2022. Methods: An analytical cross-sectional study was conducted, analyzing death records from the National Institute of Statistics and Geography’s general mortality databases. Simple frequencies and incidence rates per 100,000 inhabitants by sex, year, and state of the Mexican Republic were calculated. Mortality was evaluated by age groups and geographic areas, and bivariate logistic regression models with sociodemographic variables were performed. Results: Records of 229,182 homicides in Mexico were analyzed, with a median age of 33 years, interquartile range 18. A total of 203,898 (88.96%) were men and 25,284 (11.04%) were women. The majority of deaths occurred in public places and were caused by firearms; women had a higher percentage of homicides at home. States with high incidence rates for both sexes were Chihuahua, Zacatecas, Michoacán, Colima, and Estado de México. The total years of life lost were 9.19 million years. The national incidence of homicides in men showed an upward trend from 2015 to 2019; however, in the case of women, this incidence increased in various age groups during the study period. Occupation, education, marital status, and place of occurrence had significant associations in the logistic regression models. Conclusions: This study provides a spatial-temporal characterization of homicides in Mexico between 2015 and 2022, highlighting the high incidence in men and the upward trend in certain age groups among women. These findings underscore the need for preventive measures and public policies to address this issue in a multisectoral manner.