Introduction: An increase in antibiotic resistance and a corresponding decrease in antimicrobial discovery have directed researchers towards alternative therapies, including plant-based medicines. However, synergistic combinations of plant extracts with conventional antibiotics are a far more effective approach in overcoming resistance and potentiating the activity of antibiotics that are otherwise ineffective against resistant bacterial strains. Methods: In this study, Petalostigma spp. (native Australian medicinal plants) extracts were combined with a range of conventional antibiotics and tested against various microbial triggers of autoimmune diseases. The fruit and leaves were extracted separately with solvents of varying polarity and investigated for the ability to inhibit bacterial growth using disc diffusion and liquid dilution MIC techniques. Results: The methanolic and water extracts showed low to moderate inhibitory activity against several microbes. However, combinations of the mid-low polarity extracts with conventional antibiotics proved significantly more effective in inhibiting the growth of Proteus mirabilis and Acinetobacter baylyi (bacterial triggers of rheumatoid arthritis and multiple sclerosis respectively). In total, 14 different combinations proved to be synergistic. Notably, two antibiotics (chloramphenicol and erythromycin) with no inhibitory activity against P. mirabilis alone were shown to have substantial activity when tested in combination with Petalostigma spp. extracts. Conclusion: Although the mechanisms of synergy are still unclear, studies indicate that compounds within Petalostigma spp. may mimic the actions of resistance modifying agents, thus potentiating the activity of several antibiotics that are relatively ineffective alone. Isolation of these agents may be highly beneficial in drug design against several bacteria including the microbial triggers of rheumatoid arthritis and multiple sclerosis.