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Background: Sexually transmitted infections (STIs) and Human immunodeficiency virus (HIV) share a complex bidirectional relationship, however, population prevalence and the association between the presence of STIs and HIV in a high HIV burden district in KwaZulu-Natal, South Africa is not known. Methods: A total of 9812 participants aged 15–49 years were enrolled in a cross-sectional population-based household survey. Participants completed a structured questionnaire and provided first-pass urine (males) or self-collected vulvo-vaginal swabs (females) for the detection of STIs. Results: Prevalence of herpes simplex virus type-2 (HSV-2) was 57.8%, syphilis was 1.6%, Neisseria gonorrhoeae was 2.8%, Chlamydia trachomatis was 7.1%, Trichomonas vaginalis was 9.0%, Mycoplasma genitalium was 5.5% and HIV was 36.3%. HIV positive status was associated with an increased probability of having M. genitalium (aPR = 1.49, 95% CI 1.02–2.19) among males and syphilis (aPR = 2.54, 95% CI 1.32–4.86), N. gonorrhoeae (aPR = 2.39, 95% CI 1.62–3.52), T. vaginalis (aPR = 1.70, 95% CI 1.43–2.01) and M. genitalium (aPR = 1.60, 95% CI 1.15–2.22) among females. HIV viral load ≥400 copies per mL was associated with an increased probability of N. gonorrhoeae (aPR = 1.91, 95% CI 1.36–2.70), C. trachomatis (aPR = 1.52, 95% CI 1.12–2.05) and M. genitalium (aPR = 1.83, 95% CI 1.27–2.63). Conclusions: The high prevalence of STIs and the association between STIs and HIV, and HIV viral load underscores the public health implications of sustained transmission risk of STIs and HIV. These findings highlight the urgent need for expanding STI surveillance and implementing interventions to monitor and reduce the STI burden.