Background: Scaevola spinescens was traditionally used by Australian Aborigines to treat a variety of conditions including bacterial and viral infections, inflammation and cancer. Conventional antibiotics are amongst the most commonly prescribed groups of drugs in allopathic medicine. Therefore, these therapies may be used concurrently by practitioners of complementary medicine and there is a need to evaluate their effects in combination. Methods: Plant extracts were prepared using solvents of varying polarity and subjected to qualitative phytochemical screening analysis. Antimicrobial activity was assessed using disc diffusion and liquid dilution minimum inhibitory concentration (MIC) assays against a panel of pathogenic triggers of some autoimmune diseases. Interactions between the S. spinescens extracts and conventional antibiotics were studied and classified by determining the sum of the fractional inhibitory concentration (ΣFIC). Synergistic interactions were further examined across a range of ratios using isobolograms analysis. The toxicity of the individual samples and of the combinations was assessed using the Artemia lethality assay (ALA) and an MTS HDF cell viability assays. Results: Methanolic, aqueous and ethyl acetate extracts showed moderate to good inhibitory activity against several bacterial pathogens known to trigger autoimmune inflammatory diseases in genetically susceptible individuals. However, combinations of the methanolic, aqueous, ethyl acetate and hexane extracts with conventional antibiotics proved significantly more effective in inhibiting the growth of Klebsiellia pneumoniae and Streptococcus pyogenes (bacterial triggers of ankylosing spondylitis and rheumatic fever respectively). In total, 4 combinations proved to be synergistic, all of which contained tetracycline as the conventional antibiotic component. Furthermore, all conventional antibiotics and S. spinescens leaf extracts were determined to be nontoxic when tested alone in the Artemia nauplii and HDF bioassays. Combining the extracts and antibiotics did not significantly affect the toxicity of the combinations. Conclusion: S. spinescens extracts were effective inhibitors of the growth of several bacterial triggers of autoimmune inflammatory diseases when tested alone. Additionally, the methanolic, aqueous and ethyl acetate extracts potentiated the activity of tetracycline against bacterial otherwise resistant to its actions. Isolation of the synergising compounds in these extracts may be beneficial in drug design against several bacteria including the microbial triggers of ankylosing spondylitis and rheumatic fever.