Antibiotic resistance is one of the biggest challenges facing medical researchers. Due to the decline in the discovery of new antimicrobial agents and an increase in antibiotic resistance, medical researchers have focused on alternative therapeutic treatments. Combinational therapies that involve medicinal plants and conventional antibiotics can address the issue of increasing resistance and may help reactivate drugs that are otherwise ineffective. Terminalia sericea, Terminalia prunioides and Terminalia gazensis are native South African medicinal plants with known antimicrobial properties. However, very few studies have been performed on the combination of Terminalia sericea, Terminalia prunioides and Terminalia gazensis with conventional antibiotics. This research project aimed to study the interactive antimicrobial activity of Terminalia sericea, Terminalia prunioides and Terminalia gazensis in combination with conventional antibiotics, against gastrointestinal pathogens including antibiotic resistant strains. The leaves of each plant were extracted by using solvents of varying polarity. Antimicrobial screenings were performed using disc diffusion assays whereas the interactive antimicrobial activity was examined by a microplate liquid dilution assay. Synergistic combinations of extracts and antibiotics were tested across various ratios and the optimal ratios were determined. Extract toxicities were also assessed using an Artemia franciscana nauplii lethality assay. The antimicrobial results showed that the T. gazensis methanol extract by itself had zones of inhibition 8 ± 1 mm against both the sensitive strain of E. coli and approximately the same zone of inhibition against ESBL E. coli. This indicates that the extract may function via different antibiotic mechanisms to the ß-lactam antibiotic. The zone of inhibition of the T. methanol extract against K. pneumoniae was 10.6 ± 0.6 mm. The zone of inhibition produced by the T. gazensis water extract against K. pneumoniae was 14 ± 1.5 mm, comparing favorably to the positive control antibiotic, chloramphenicol, that produced a zone of inhibition of 15.3 ± 0.6 mm. The T. gazensis methanol extract possessed the most potent inhibitory activity (MIC = 862.5 μg/mL) against MRSA in the liquid dilution assay, although the T. prunioides methanol extract was active towards K. pneumoniae in the liquid dilution assay (MIC = 1325 μg/mL). The highest MICs (and thus the least active) in the disc diffusion assay was observed for S. aureus and S. newport (MIC = 8550 μg/mL). Terminalia sericea water extracts did not show any inhibitory activity against any of the pathogens tested. The interactive antimicrobial activity of Terminalia sericea, Terminalia prunioides and Terminalia gazensis and conventional antibiotics revealed that 48 combinations produce synergistic effects, 45 produced additive effects, 41 produced non-interactive effects and 26 produced antagonistic effects. Most of the antagonism was seen with gentamicin, which is unsurprising given that gentamicin is a relatively new drug and most bacteria strains have not yet developed resistance against the drug. Therefore, the presence of extracts may disrupt gentamicin mechanisms of action. Finally, toxicity experiments using the Artemia nauplii assay revealed that almost all extracts were non-toxic at 1000 μg/mL. The results of this study suggest that resistance modifying agents in the Terminalia spp. extracts may be yielding synergistic enhancements in antibacterial activities when combined with antibiotics, including against resistant bacteria, indicating that the plant extracts contain molecules acting as β-lactamase or efflux pump inhibitors. This research thus provides insights into the possible interactions between extracts of medicinal plants such as T. prunioides, T. gazensis and T. sericea in combination with conventional antibiotics, revealing their potential as therapeutic agents. Although the mechanisms underlying the synergy are unknown, studies have reported active compounds within the T. prunioides, T. gazensis and T. sericea which can potentially mimic the action of a resistance-modifying agent, hence increasing the activity of antibiotics that are inactive when used alone. Thus, a combinational approach may not only enhance the effectiveness of drugs but may also reduce side effects of antibiotics and help prevent the further emergence of drug resistant bacteria. Future studies should be directed at gaining a more detailed understanding of the mechanisms that govern synergistic inhibition of gastrointestinal bacterial growth by these plant extracts when combined with antibiotics. The identification resistance modifying agents from Terminalia sericea, Terminalia prunioides and Terminalia gazensis may also inform drug design strategies to enable the development of novel, effective antibiotics.