This study aimed to analyse the patterns, trends, genomic characteristics, and key determinants of dengue virus (DENV) infections and associated deaths in South Asia from 2000 to 2023. We collected data from the World Health Organization dengue surveillance dashboard and the health ministries of respective countries, and publicly available data from eight South Asian (SA) countries. Descriptive measures, data visualization techniques, and time series analysis were used to identify key patterns and trends of DENV. A time-scaled phylogenetic analysis was carried out to explore the genomic epidemiology and evolution of DENV. A generalized linear model (GLM) was fitted to identify climatic, demographic, and socioeconomic factors. Between 2000 and 2023, SA countries showed a sharp increase in dengue cases and deaths, contributing to 6.5% of cases and 11.07% of deaths caused by DENV globally. The total cases in the region are projected to grow by approximately 40%, and total deaths by 61% by 2033. The predominant genotypes were DENV2/II, DENV3/I, and DENV3/III. GLM underscores climatic, demographic, and socioeconomic factors associated with DENV infection and deaths. The findings urge intensified public health measures emphasising the need for comprehensive interventions, including vector control, climate adaptation, and strengthened healthcare systems to de-escalate the situation.