Bacteria and fungi are frequent causes of serious opportunistic infections worldwide. Several effective antibiotic drugs are in the market. However, drug-resistance, side effects and cost of such antibiotics limits their usefulness in disease management. About 80% of the world’s inhabitants still rely on traditional medicines based on herbal plants for their primary healthcare. Anti-infective agents from plant origin are preferred because they have no side effects and are readily available. Rhus species have several applications both in traditional and contemporary medicine yet scientific data to support such uses is scanty. The aim of this study was to determine the efficacy of Rhus natalensis Krauss and Rhus ruspolii Engl in management of microbial infections. Plant extracts were subjected to cytotoxicity, antibacterial and antifungal assays using standard methods. LC50 values n-hexane, dichloromethane, ethyl acetate and methanol extracts were 7.15, 13.35, 4.80, 16.70 and 42.53, 22.3, 19.70, 25.70 μg/ml for R. natalensis and R. ruspolii, respectively. The plant extracts showed moderate activities (P ≤ 0.05) against the tested bacteria (Gram-positive and Gram-negative) and fungi. In all the tests, bioactivities of the extracts were lower compared to activity of standard drugs which were used as controls. These findings support the use R. natalensis and R. ruspolii in treating bacterial and fungal infections. Further studies aimed at isolation and characterization of the bioactive principles is necessary with the hope of getting better antimicrobial agents. It is also necessary to determine the mechanism of action of the extracts.