Abstract: Background and Objective: Gongronema latifolium and Vernonia amygdalina are medicinal plants that have been used in the treatment of nausea, hypertension, diabetes, stomach ache, high cholesterol level etc. However this research was set out to access comparatively the immuno-stimulatory effect of ethanol leaf extract of Gongronema latifolium and Vernonia amygdalina in cyclophosphamide immuno-suppressed rats. Materials and Methods: Thirty Wistar albino rats of 5 rats per group were used for this study and were divided into 6 groups. Group 1 rats were normal control; group 2 (positive control) rats were administered cyclophosphamide only, at the dose of 50 mg kg–1 b.wt. i.p. Group 3 rats were administered low dose (400 mg kg–1 b.wt.) of the Vernonia amygdalina leaf extract after cyclophosphamide induction while group 4 rats were administered high dose (600 mg kg–1 b.wt.) of the extract after cyclophosphamide induction. Group 5 rats were administered low dose (400 mg kg–1 b.wt.) of Gongronema latifolium leaf extract after cyclophosphamide induction while group 6 rats were administered high dose (600 mg kg–1 b.wt.) of the extract after cyclophosphamide induction. The results were analyzed using one way analysis of variance (ANOVA) using SPSS version 20. Results: Treatment with Vernonia amygdalina and Gongronema latifolium leaf extract (group 3, 4 and group 5, 6 respectively) showed a significant increase (p<0.05) in SOD activity, glutathione and vitamin C concentrations when compared with group 2 rats treated with cyclophosphamide only. More so treatment with Vernonia amygdalina and Gongronema latifolium leaf extract (group 3, 4 and group 5, 6 respectively) showed a significant decrease (p<0.05) in the liver marker enzymes (ALT, AST and ALP) when compared to group 2 rats treated with cyclophosphamide only, however group 2 rats showed a significant decrease (p<0.05) in total protein concentration and a significant increase (p<0.05) in the total cholesterol concentration and triacylglycerol concentration when compared to the treatment groups. Conclusion: Comparatively, these findings indicate that Vernonia amygdalina may have better antioxidant properties and also exhibited more potency in inhibiting liver damage by lowering the liver marker enzymes compared to Gongronema latifolia.