The South African medicinal plant, Sutherlandia frutescens (L.) R.Br. (also known as Lessertia frutescens) is traditionally used to treat conditions in which inflammation is a central feature. Aqueous and organic extracts of Sutherlandia frutescens have immune-regulatory, anti-inflammatory and antioxidant properties, potentially underlying its wide ranging medicinal activities. In this review, data relating to the effects of Sutherlandia frutescens extracts on the function of two major macrophage sub-populations involved in inflammation and immune responses is addressed. Findings are related to chronic inflammatory states found in obesity, type 2 diabetes and the metabolic syndrome, in which the roles of classically activated pro-inflammatory M1 macrophages and alternatively activated anti-inflammatory M2 macrophages have been highlighted. We evaluate potential mechanisms by which Sutherlandia frutescens extracts may regulate macrophage activation and wider metabolic immunomodulatory processes underlying these conditions and indicate potential ethnopharmacological mechanisms of action. Electronic databases from 1965 to 2019 and other literature sources, including short communications, reports, conference proceedings and theses were used to compile this review. Published work indicates that Sutherlandia frutescens has potential as a phytomedicine to treat inflammation and stimulate wound healing, via down-regulation of pro-inflammatory macrophage activity. We propose that this involves regulation of MAPK, p38 and NFκB, Akt-independent IKK and Akt-dependent GSK3β signalling pathways. Control of such signals could lead to modulation of inflammatory responses in local macrophages and regulation of macrophage apoptosis, through ERK1/2 phosphorylation. This would stimulate recruitment of macrophages in resolution of inflammation and wound repair. Differing findings for aqueous and organic extracts indicate that care is needed in sourcing plant material, choice of extract procedures, systemic or topical application and dosage used in clinical situations. Currently there is no single bioactive phytochemical identified in Sutherlandia frutescens that accounts for the anti-inflammatory activity. We postulate that this action is due to the combined effect of several phytochemicals.