Cardiovascular-related complications are on the rise in people with HIV/AIDS (PWH); however, the relationship among HIV and antiretroviral therapy (ART)-related parameters, cardiovascular risk, and cardiac electrical activity in PWH remain poorly studied, especially in sub-Saharan African populations. We investigated whether HIV and ART are associated with cardiometabolic and cardiac electrical activity in PWH from Worcester in the Western Cape Province, South Africa. This was a cross-sectional study with HIV-negative (HIV−, n = 24) and HIV-positive on ART (HIV+/ART+, n = 63) participants. We obtained demographic, lifestyle, and medical history data and performed anthropometric, clinical assessments, and blood/urine biochemistry. We performed multiple stepwise linear regression analyses to determine independent associations among HIV, ART, cardiometabolic, and electrocardiographic (ECG) variables. HIV+/ART+ independently associated with a lower body mass index (p = 0.004), elevated gamma-glutamyl transferase levels (β: 0.333 (0.130–0.573); p = 0.002), and elevated alanine aminotransferase levels (β: 0.427 (0.224–0.629); p < 0.001) compared to HIV−. Use of second-line ART was positively associated with high-sensitivity C-reactive protein (p = 0.002). Although ECG parameters did not differ between HIV− and HIV+/ART+, viral load positively associated with p-wave duration (0.306 (0.018–0.594); p = 0.038), and longer HIV duration (≥5 years) with ST-interval (0.270 (0.003–0.537); p = 0.047) after adjusting for confounding factors. Our findings suggest that HIV and ART are associated with mixed effects on this population’s cardiometabolic profile and cardiac electrical activity, underpinning the importance of cardiovascular risk monitoring in PWH.