An increase in antibiotic resistance and a corresponding decrease in antimicrobial drug discovery have resulted in researchers focussing on alternative therapies, including plant based medicines. The development of bacterial strains resistant to β-lactam, including resistance to the second generation drugs methicillin, is particularly concerning and has rendered many common therapies ineffective or of substantially decreased efficacy. New antibiotic therapies are urgently needed. The antibacterial activity of selected southern African Combretum spp. leaf extracts towards β-lactam resistant and sensitive bacterial strains was investigated by disc diffusion assays and quantified by broth microdilution Minimum inhibitory concentration (MIC) assays. Toxicity was evaluated by testing Artemia nauplii mortality and human dermal fibroblast (HDF) cytotoxicity assays. The gas chromatography coupled to Mass spectrometry (GC-MS) headspace analysis was used to identify volatile terpenoid components. The leaf extracts of all Combretum spp. displayed noteworthy growth inhibitory activity against all of the bacteria tested, including against Methicillin resistant Staphylococcus aureus MRSA, and the extended spectrum β-lactamase (ESBL) strains of E. coli and K. pneumoniae. Combretum heroense leaf extract had particularly good (MICs = 170-680 μg/mL) antibacterial activity against all bacterial strains. Notably, this extract was a better inhibitor of MRSA than of the β-lactam sensitive strain of S. aureus. The Combretum vendae extract was also a good inhibitor of the MRSA and ESBL strains. Noteworthy antibacterial activity (MICs 120-890 μg/mL) was also noted for Combretum collinum and Combretum molle extracts against all bacteria, and for the Combretum bracteosum and Combretum erythrophyllum extracts against the MRSA and ESBL strains (500-1625 μg/mL). All extracts were non-toxic in the Artemia nauplii lethality assay (ALA) and HDF assays and the calculated therapeutic indexes (TIs) indicated their safety for use as antibiotic chemotherapies. The GC-MS headspace analysis identified and highlighted several noteworthy monoterpenoids which had antibacterial properties. In particular, cineole, terpineol, camphor, borneol and limonene were present in relative abundance in all Combretum spp. extracts. Further phytochemical and mechanistic studies of these extracts are warranted.