The main objective of this study was to analyse the space–time epidemiological differences by sex during the 2009–2020 period in the total mortality recorded among residents in each of the 25 districts of the Genoa municipality, net of the age effect. The analysis was based on official statistical data relating to total mortality and on the resident population. An estimate of the expected deaths was made to calculate the sex-specific age-standardised mortality ratio (SMR). The temporal trends and age-standardized death rates (SDRs) with respect to those of the European population specific to sex and calendar year were identified for each district. Over the entire observation period, the SMR for males ranged from 124.4 (Cornigliano) to 82.0 (Albaro); for females, the values ranged between 133.4 (Cornigliano) and 85.6 (Nervi-Quinto-S. Ilario). Between 2019 and 2020, Genoa recorded an increase in SDR of 24.5%, more pronounced in males (+26.7%) than in females (+22.4%). This epidemiological methodology is replicable and allows to quickly identify spatial, temporal, sex, and age differences in the general mortality within a municipality.