Abstract: Background and Objective: Cadmium is a heavy metal that accumulates with time in different tissues of the body like central nervous system, kidney, liver etc. causing toxic effects especially to the brain and has a very long biological half-life. The objective of this study was to explore the neuroprotective effect of cadambine an indole alkaloid against cadmium-induced toxicity. Materials and Methods: Three cell lines namely N2A, SH-SY5Y and primary brain neonatal rat cells were used in this study. Cell viability and neuroprotection assays were assessed by MTT assay to determine the effect of cadmium and cadambine. Changes in the intracellular calcium levels, ROS and mitochondrial membrane potential were determined by flow cytometer. Western blotting was done to analyse the effects of cadmium and cadambine on pro-apoptotic and anti-apoptotic genes. Student’s t-test was used to compare the data. Results: In this study, it was confirmed that cadmium induced toxicity was reversed by cadambine. Cadambine increased the viability of cells treated with of cadmium induced toxicity. Furthermore, cadmium treatment led to generation of ROS, increased calcium levels, loss of MMP and increase in the expression of pro-apoptotic proteins. Interestingly, these effects was reversed by cadambine in primary brain neonatal rat cells. Conclusion: These findings led us to the conclusion that exposure to cadmium induces neurotoxic effects in brain and cadambine not only reversed the toxic effects of cadmium but also led to inhibition of cadmium-induced apoptosis. Based on this data, cadambine can further be investigated as potent neuroprotective agent.