It has become increasingly popular to use medicinal plants in cancer treatments since researchers have identified anticancer compounds such as paclitaxel, vincristine, and camptothecin in plants. Despite the progress made so far, the challenge of efficacy, selectivity and toxicity persists. In the current study, Erythrina caffra, a commonly used medicinal plant in South Africa was assessed for its anticancer potential. The plant leaves were initially subjected to solvent extraction using N-hexane, dichloromethane, ethylacetate and methanol. The extracts were evaluated for their antioxidant, anticancer, and cell migration inhibitory properties. The phytochemicals were then tentatively identified using gas chromatography mass spectrometry. Sequel to the phytochemical identification, a variety of in silico methods including molecular docking, Quantitative structure-activity relationship modeling (QSAR), and binding free energy calculations were used to screen for potential modulators of the cancer proteins MDM2, CDK2 and CDK6. The compounds showing high inhibitory activity from the screening were assessed for leadlikeness property to identify their suitability as drug candidates. The DCM extract had the best antioxidant and anticancer potential and the in silico analysis revealed drug-like compounds such as 5-bromovaleric acid, 2-methyloct-5-yn-4-ylester, liquiritigenin, di-isooctyl phthalate and 8-ethyl-6,7-dimethyl- lumazine which could act on one or more of the cancer targets to elicit potential anticancer effects. These compounds were also shown to have good oral bioavailability and low toxicity. Overall, the E. caffra extract exhibited significant anticancer potential and contained lead compounds that can be developed in the future as drug candidates in the treatment of cancer.