The purpose of the study was to investigate the bioactivity of extracts of selected plant species used to treat sexually transmitted diseases (STD’s) in southern Africa. As the emergence of drug resistance pathogens in STD’s treatment and potential side effects of synthetic drugs demands the discovery of newer and safer drugs, the exploration of newer anti-microbial substances from natural sources may serve as promising alternatives. Ethanol extracts of twelve medicinal plants used traditionally to treat sexually transmitted diseases and 3 flavonoids (F1, F2 and F3) isolated from Elaeodendron transvaalense were evaluated for their antimicrobial properties against one fungus and three bacteria. To determined anti-inflammatory activities of the extracts and compounds, the inhibitory effect was measured on the pro-inflammatory enzyme, 15-lipoxygenase (15-LOX). The extracts and compounds were also investigated for their anti-HIV activity against recombinant HIV-1 enzyme using non-radioactive HIV-RT colorimetric assay. Acacia karoo and Rhoicissus tridentata extracts indicated good anti-microbial activity with MIC values ranging between 0.4 and 3.1 mg/mL. Extracts of Jasminum fluminense, Solanum tomentosum, F2 and F3 had good anti-inflammatory activity with IC50 less than positive control quercetin (IC50 = 48.86 μg/mL). Acacia karoo and F3 exhibited moderate HIV RT inhibition activity of 66.8 and 63.7% respectively. Rhoicissus tridentata and Terminalia sericea had the best RT inhibition activity (75.7 and 100%) compared to that of the positive control doxorubicin (96.5%) at 100 μg/mL. The observed activities may lead to new multi-target drug against sexually transmitted diseases.