With a long epidemic history and a large number of dengue cases, Guangzhou is a key city for controlling dengue in China. The demographic information regarding dengue cases, and the genomic characteristics of the envelope gene of dengue viruses, as well as the associations between these factors were investigated from 2010 to 2019, to improve the understanding of the epidemiology of dengue in Guangzhou. Demographic data on 44,385 dengue cases reported to the Notifiable Infectious Disease Report System were analyzed using IBM SPSS Statistics v. 20. Dengue virus isolates from patient sera were sequenced, and phylogenetic trees were constructed using PhyML 3.1. There was no statistical difference in the risk of dengue infection between males and females. Unlike other areas in which dengue is endemic, the infection risk in Guangzhou increased with age. Surveillance identified four serotypes responsible for dengue infections in Guangzhou. Serotype 1 remained prevalent for most of the study period, whereas serotypes 3 and 4 were prevalent in 2012 and 2010, respectively. Different serotypes underwent genotype and sublineage shifts. The epidemiological characteristics and phylogeny of dengue in Guangzhou suggested that although it has circulated in Guangzhou for decades, it has not been endemic in Guangzhou. Meanwhile, shifts in genotypes, rather than in serotypes, might have caused dengue epidemics in Guangzhou.