The geographical concentration of criminal violence is closely associated with the social, demographic, and economic structural characteristics of neighborhoods. However, few studies have investigated homicide patterns and their relationships with neighborhoods in South Asian cities. In this study, the spatial and temporal patterns of homicide incidences in Karachi from 2009 to 2018 were analyzed using the local indicators of spatial association (LISA) method. Generalized linear modeling (GLM) and geographically weighted Poisson regression (GWPR) methods were implemented to examine the relationship between influential factors and the number of homicides during the 2009–2018 period. The results demonstrate that the homicide hotspot or clustered areas with high homicide counts expanded from 2009 to 2013 and decreased from 2013 to 2018. The number of homicides in the 2017–2018 period had a positive relationship with the percentage of the population speaking Balochi. The unplanned areas with low-density residential land use were associated with low homicide counts, and the areas patrolled by police forces had a significant negative relationship with the occurrence of homicide. The GWPR models effectively characterized the varying relationships between homicide and explanatory variables across the study area. The spatio-temporal analysis methods can be adapted to explore violent crime in other cities with a similar social context.