Tuberculosis (TB) is a threat to a large population across the globe. Rapanea melanophloeos (L.) Mez, commonly known as the Cape beech, is a plant that is traditionally used in the treatment of tuberculosis and TB-related symptoms. The aim of this study, was to evaluate the pharmacological effects of a leaf ethanolic extract (1:10, w:v) of R. melanophloeos, as well as different polarity partitions, in conjunction with a fluoroquinolone antimycobacterial drug, ciprofloxacin. The bioassays in this study included the antimycobacterial, antibiofilm and synergistic potential against M. smegmatis. Secondly the antiproliferative and hepatoprotective effect on hepatocytes (HepG2), and, lastly, a potential mechanistic investigation on mycothione, glutathione and thioredoxin reductases. The hexane fraction from the ethanolic plant extract showed relatively good antibiofilm activity with a mean IC50 value of 128.25±4.09 μg/mL. The drug-herb interaction activity of the extract was tested against ciprofloxacin, and it was found that the plant extract acted antagonistically towards the standard drug (FIC > 4). Antiproliferative and hepatoprotective tests were conducted on HepG2 hepatocytes to test the effects on cell viability. The plant was not toxic to the cells but showed no significant hepatoprotective activity against drug-induced hepatotoxic injury, in comparison to the positive control silymarin. Furthermore, the plant extract was tested against glutathione, mycothiol and thioredoxin reductase (human and bacterial analogs) for its inhibitory activity. Rapanea melanophloeos showed higher affinity for the glutathione and mycothiol reductase with relatively high inhibitory activity against the enzymes. The findings from this study indicate the potential adverse effects and drug-herb interactions, associated with the use of R. melanophloeos in the treatment of TB. In addition, this study emphasizes the importance of herb indications and drug interactions, and the term “natural” or “herbal” does not coincide with safe.