Medicinal plants play a huge role in the treatment of various diseases in the Limpopo province (South Africa). Traditionally, concoctions used for treating tuberculosis and cancer are sometimes prepared from plant parts naturally occurring in the region, these include (but not limited to)Schotia brachypetala, Rauvolfia caffra, Schinus molle, Ziziphus mucronate,andSenna petersiana.In this study, the aim was to evaluate the potential antimycobacterial activity of the five medicinal plants againstMycobacterium smegmatismc2155,Mycobacterium aurumA + , andMycobacterium tuberculosisH37Rv, and cytotoxic activity against MDA-MB 231 triple-negative breast cancer cells. Phytochemical constituents present inR. caffraandS. mollewere tentatively identified by LC-QTOF-MS/MS as these extracts showed antimycobacterial and cytotoxic activity. A rigorous Virtual Screening Workflow (VSW) of the tentatively identified phytocompounds was then employed to identify potential inhibitor/s ofM. tuberculosispantothenate kinase (PanK). Molecular dynamics simulations and post-MM-GBSA free energy calculations were used to determine the potential mode of action and selectivity of selected phytocompounds. The results showed that plant crude extracts generally exhibited poor antimycobacterial activity, except forR. caffraandS. mollewhich exhibited average efficacy againstM. tuberculosisH37Rv with minimum inhibitory concentrations between 0.25–0.125 mg/mL. Only one compound with a favourable ADME profile, namely, norajmaline was returned from the VSW. Norajmaline exhibited a docking score of –7.47 kcal/mol, while, pre-MM-GBSA calculation revealed binding free energy to be –37.64 kcal/mol. All plant extracts exhibited a 50% inhibitory concentration (IC50) of < 30 μg/mL against MDA-MB 231 cells. Flow cytometry analysis of treated MDA-MB 231 cells showed that the dichloromethane extracts fromS. petersiana,Z. mucronate,and ethyl acetate extracts fromR. caffraandS. molleinduced higher levels of apoptosis than cisplatin. It was concluded that norajmaline could emerge as a potential antimycobacterial lead compound. Validation of the antimycobacterial activity of norajmaline will need to be performed in vitro and in vivo before chemical modifications to enhance potency and efficacy are done.S. petersiana,Z. mucronate,R.caffraandS. mollepossess strong potential as key contributors in developing new and effective treatments for triple-negative breast cancer in light of the urgent requirement for innovative therapeutic solutions.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12906-023-04041-5.