Medicinal plants remain a productive source of bioactive molecules for antimicrobial drug discovery. This study compared the phytochemical composition and antibacterial activity of aqueous, methanolic, chloroform and hexane leaf extracts of Simarouba glauca DC. and assessed the cytotoxicity of the methanolic extract towards mammalian cells. Extracts were prepared by Soxhlet extraction and screened qualitatively for the major classes of secondary metabolites. Antibacterial activity was determined against Staphylococcus aureus, Streptococcus mutans, Escherichia coli and Pseudomonas aeruginosa by the agar well diffusion method. Cytotoxicity of the methanolic extract in L929 mouse fibroblasts was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Alkaloids, carbohydrates and terpenoids were detected in all four extracts, whereas flavonoids, phenolic compounds and tannins were largely confined to the aqueous and methanolic extracts. The aqueous extract produced the largest zone of inhibition, 20.33 ± 0.58 mm against S. aureus. Two-way analysis of variance confirmed a significant effect of extraction solvent on inhibition for every organism tested (p < 0.001), the aqueous extract exceeding the methanolic, chloroform and hexane extracts in all pairwise comparisons; the hexane extract was inactive throughout. Fibroblast viability remained above 70 % at 100 µg/mL of the methanolic extract and the IC50 of 155.1 µg/mL is an extrapolated value, since 50 % inhibition was not reached within the range tested. Under ISO 10993-5 criteria the extract is therefore classified as non-cytotoxic. The combination of measurable antibacterial activity in the polar extracts with low toxicity towards mammalian fibroblasts identifies the aqueous and methanolic leaf extracts of S. glauca as suitable starting material for bioassay-guided fractionation and for the development of plant-derived topical and oral-care antibacterial formulations.