Little previous phytochemical investigation has been conducted on South African Sterculiaceae species used in traditional medicine. In this study, five species, varying in growth type (small herbs, shrubs and large trees) and traditional usage were investigated. The species screened were Cola greenwayi Brenan, Cola natalensis Oliv., Dombeya burgessiae Gerr. ex Harv., Dombeya cymosa Harv. and Hermannia depressa N.E.Br. Extracts were screened for alkaloids, cardiac glycosides, cyanogenic glycosides, saponins and tannins. The probable presence of bufadienolides in the leaf material of Dombeya burgessiae and Dombeya cymosa was determined. Alkaloids, cyanogenic glycosides and saponins were absent in all the plant material investigated. Tannins were detected in the leaf extract of Cola greenwayi and in the leaves, stems and roots of Hermannia depressa. Extracts were screened for anti-inflammatory and antibacterial activity using the cyclooxygenase-1 (COX-1) inhibition assay and the microdilution antibacterial assay. The ethanol and dichloromethane extracts of Cola greenwayi, Dombeya burgessiae and Dombeya cymosa, and the dichloromethane extracts of Hermannia depressa showed the highest levels of COX-1 inhibition. It is possible that the high levels observed may be due to the presence of tannins in some of the extracts. Generally, all the aqueous extracts exhibited low activity. Similarly, no antibacterial activity was observed with the aqueous extracts, although some mild activity was exhibited with some of the ethanol and ethyl acetate extracts. Following the general phytochemical and pharmacological screening, extracts showing antibacterial activity were further purified using bioassay-guided fractionation. Dombeya rotundifolia (Hochst.) Planch., which was screened in a previous study, was also included in the isolation of active compounds. A bioautographic assay, using Staphylococcus aureus, was used to detect the presence of the antibacterial compounds. These were isolated and identified as fatty acids.