Spatial analysis at different levels can help understand spatial variation of human immunodeficiency virus (HIV) infection, disease drivers, and targeted interventions. Combining spatial analysis and the evaluation of the determinants of the HIV burden in Southern African countries is essential for a better understanding of the disease dynamics in high-burden settings. The study countries were selected based on the availability of demographic and health surveys (DHS) and corresponding geographic coordinates. We used multivariable regression to evaluate the determinants of HIV burden and assessed the presence and nature of HIV spatial autocorrelation in six Southern African countries. The overall prevalence of HIV for each country varied between 11.3% in Zambia and 22.4% in South Africa. The HIV prevalence rate was higher among female respondents in all six countries. There were reductions in prevalence estimates in most countries yearly from 2011 to 2020. The hotspot cluster findings show that the major cities in each country are the key sites of high HIV burden. Compared with female respondents, the odds of being HIV positive were lesser among the male respondents. The probability of HIV infection was higher among those who had sexually transmitted infections (STI) in the last 12 months, divorced and widowed individuals, and women aged 25 years and older. Our research findings show that analysis of survey data could provide reasonable estimates of the wide-ranging spatial structure of the HIV epidemic in Southern African countries. Key determinants such as individuals who are divorced, middle-aged women, and people who recently treated STIs, should be the focus of HIV prevention and control interventions. The spatial distribution of high-burden areas for HIV in the selected countries was more pronounced in the major cities. Interventions should also be focused on locations identified as hotspot clusters.