Vincristine sulphate (VCR), a dimeric alkaloid isolated from the periwinkle plant Catheranthus roseus, is used for the treatment of several forms of malignancies. This study aimed to evaluate its hepato-renal toxicity in rats and the possible protective role of broccoli and mustard seeds extracts. Seven groups of Sprague-Dawley rats were used; 3 groups served as negative and positive controls, and four groups were treated either with vincristine alone or with vincristine plus broccoli, and/or mustard seeds, twice a week for 8 consecutive weeks. Histological, histochemical and biochemical changes in the liver and kidney were investigated. The expression of the glial cell line-derived neurotrophic factor (GDNF) and its receptor alpha-1 (GFRα-1) was investigated by immunohistochemistry. Histological and histochemical observations revealed histopathological changes in the form of cytoplasmic degeneration, nuclear pyknosis and cell necrosis in both liver and kidney tissues of vincristine-treated animals. Depletion in glycogen and total protein levels was recorded. In addition, the immuno-expression of both GDNF and GFRα-1 was downregulated. Biochemical data indicated a significant increase in oxidative stress markers, reduction in antioxidant enzymes as well as increase in the parameters of liver and kidney functions. On the other hand, broccoli and mustard treatment prominently attenuated the vincristine-induced histopathological and histochemical changes and almost restored the normal level of biochemical parameters. To conclude, these results suggest that long term use of vincristine may be toxic and results in complex liver and kidney damage. Furthermore, broccoli and mustard seeds may be useful in combating oxidative stress-induced liver and kidney injuries resulting from vincristine administration.