Annona senegalensis pers, Sutherlandia frutescens (L.), and Withania somnifera (L.) are abundant plants and widely distributed in the Limpopo, Gauteng, Kwazulu-Natal, North West and Mpumalanga provinces in South Africa. The three plants are among those used by traditional healers and herbalists in South Africa for the treatment of a variety of diseases, including cancer. The current study aimed at the phytochemical screening and characterization of volatile compounds from the three medicinal plants using GC-MS. The methanol leaf extracts were subjected to phytochemical screening using standard chemical tests to detect the presence of different classes of compounds. Volatile compounds were detected by GC-MS analysis, and detected compounds were identified by comparing the MS spectral data with those of compounds deposited in the NIST Library (NIST08). Phytochemical screening indicated the presence of different secondary metabolites such as alkaloids, quinones, steroids, cardiac glycosides, coumarins, and terpenoids in all plants. GC-MS chromatograms allowed the detection and identification of 19 volatile compounds among the three plants with known bioactivities that are important in the management of life-threatening diseases such as cancer and diabetes. The results confirm the leaves of Annona senegalensis, Sutherlandia frutescens, and Withania somnifera as sources of important phytochemicals and therefore justify their use for the treatment of various diseases by traditional healers.