Although São Paulo is the most populous city in Brazil - one of the world's most violent countries - a significant reduction in its homicide mortality rate (HMR) has been detected. This study aims to estimate the effects of age, period, and birth cohort on the trend of homicide mortality according to sex in the city of São Paulo, from 1996 to 2015. An ecological study was undertaken with data on deaths by homicide for both sexes, in all age brackets, in the city of São Paulo. Poisson models were adjusted for each sex to estimate the age-period-cohort effects. In total, 61,833 deaths by homicide were recorded among males and 5,109 among females. Regardless of the period, the highest HMR occurred in the 20-24 age bracket. Higher HMRs were found in those born in the 1970s and 1980s. The complete model, with age-period-cohort effects, were the best fit to the data. The risk of death by homicide declined over the periods, with lower intensity in the final five years (2011-2015), for both males (RR = 0.48; 95%CI: 0.46; 0.49) and females (RR = 0.52; 95%CI: 0.47; 0.57). A reduction was found in the risk of homicide, regardless of the sex or age bracket, and also in recent cohorts. However, the intensity of such reductions has been decreasing over time, which suggests that the public policies adopted have limited potential to maintain these achievements.