In southern Africa, many medicinal plants are used traditionally to treat gastrointestinal disorders and other infectious diseases. Newtonia hildebrandtii and Newtonia buchananii are used for the treatment of wounds and skin conditions, and for an upset stomach. Following promising unpublished antibacterial activity against Escherichia coli, this study was undertaken to evaluate the potential efficacy of N. hildebrandtii and N. buchananii extracts in treating diarrhoea. The antimicrobial activity of N. hildebrandtii and N. buchananii extracts was determined against a panel of Gram-positive and Gram-negative bacteria and two fungi implicated in causing diarrhoea. N. buchananii had strong antimicrobial effect against Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) of 20 μg/ml and moderate activity of 40 μg/ml against Bacillus cereus. Cytotoxicity of extracts was evaluated against Vero cells and both plants were relatively non-toxic with IC50 values of 30–750 μg/ml. Selectivity index values as high as 18.75 were reached with the methanol–dichloromethane leaf extract of N. buchananii. The extracts also had good anti-inflammatory and antioxidant activities as well as acetylcholinesterase inhibition efficacy. These activities are all useful adjuncts, together with antimicrobial effects, in potential plant-based remedies to be used as diarrhoea treatments.