Bulbine frutescens, a plant native to southern Africa, is used traditionally in the management of conditions related to HIV/AIDS and to promote wound healing. This study investigated the in vitro anti-HIV and antioxidant potential of B. frutescens in order to determine its possible contribution to alleviating HIV/AIDS and its traditional success as a wound healing agent. The extract of the aerial parts of B. frutescens was tested for in vitro inhibitory activity on HIV-1 protease (PR), reverse transcriptase (RT) and integrase enzymes all of which have an essential role in the HIV replication cycle. Since antioxidants contribute to wound healing, the plant extract was studied for 2,2-diphenyl-1-picryl hydrazyl (DPPH), ferric reducing power and hydrogen peroxide (H2O2) scavenging activity. In addition, phytochemical analysis of the extract was conducted using standard procedures. The extract demonstrated good inhibitory activity against HIV-1 PR and RT with IC50 values of 0.18 ± 0.01 and 0.52 ± 0.03 mg/mL, respectively. It also demonstrated potent antioxidant activity with IC50 values of 17.94 ± 0.72 and 26.21 ± 0.39 μg/mL for DPPH and H2O2, respectively. The reducing power of B. frutescens extract was found to be concentration dependent. Qualitative phytochemical screening revealed the presence of phenols, alkaloids and flavonoids. The content of one of the major component detected, flavonoids, was 71.60 ± 0.05 mg QE/g extract. This study demonstrates that B. frutescens extract has anti-HIV potential and the traditional use of the plant as a wound healing agent could be through its high antioxidant activity.