Introduction: Streptococcus pyogenes is a gram positive pathogenic bacterium which causes a variety of diseases including streptococcal pharyngitis, impetigo and rheumatic heart disease. Many Brachychiton spp. have reported uses to treat pathogenic illness and are rich in flavonoids with reported antibacterial activity. Despite this, B. rupestris leaf extracts have not previously been examined for bacterial growth inhibitory properties. Methods: The ability of B. rupestris leaf extracts to inhibit the growth of S. pyogenes was investigated by disc diffusion and growth time course assays. The growth inhibitory activity was further quantified by MIC determination. Toxicity was determined using the Artemia franciscana nauplii bioassay. Results: The methanolic and aqueous B. rupestris leaf extracts were potent inhibitors of S. pyogenes growth, with MIC values as low as 445μg/mL. The antibacterial activity of the methanolic and aqueous B. rupestris leaf extracts were further investigated by growth time course assays that showed significant growth inhibition within 1h of exposure. All extracts were determined to be nontoxic in the Artemia franciscana nauplii bioassay, indicating their safety for use in preventing S. pyogenes associated diseases caused by these pathogens. Conclusion: The lack of toxicity of the B. rupestris leaf extracts and their growth inhibitory bioactivity against S. pyogenes indicate their potential in the development of new therapies for rheumatic fever, pharyngitis, impetigo and other illnesses caused by this bacterium.