Despite access to antiretroviral therapy (ART), South Africa has a high human immunodeficiency virus (HIV) burden. Treatment outcomes among individuals on highly active ART (HAART) in KwaZulu-Natal, with a higher incidence of HIV, are not fully known. This study evaluated the impact of HAART outcomes and identified and analyzed the factors associated with the outcomes in people living with HIV and AIDS (PLWHA) in the high-incidence region of KwaZulu-Natal Province, South Africa. This retrospective medical record review was conducted at King Edward VIII Hospital in South Africa. Data analysis was performed using STATA software Version 18.0 and Microsoft Excel 2021. The estimates used were 95% confidence intervals, and a value < 0.05 was considered statistically significant. A total of 707 clinical records of PLWHA were examined and analyzed; less than half of them (44.98%,  = 318) achieved the benchmark of two consecutive instances of suppressed viral loads. The CD4 greater than or equal to 500 cells/mm at baseline average of 22.91% ( = 162) registered an increase to 48.94% ( = 346) in the 6 month and further escalated to 79.49% ( = 562) by the 12 month following ART initiation. A total of 160 deaths (mortality rate of 22.63%) were recorded within the study period. The percentage of HIV-infected patients attaining viral suppression at 6 and 12 months after initiating the treatment was respectively 44.98% and 67.04%, below the 90% target established by the Joint United Nations Program on HIV/AIDS (UNAIDS). The proportion of favorable immunological responses for individuals on ART increased over time.