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Abstract Background Exposure to cadmium is implicated in the etiology of some neurodegenerative diseases. Compounds isolated from Ipomoea cairica extract are neuroprotective. However, there is no reported neuroprotective activity of the crude extract of I. cairica (ICE). We investigated the neuroprotective activity of I. cairica extract against cadmium-induced biochemical changes in the brain of male Wistar rats. Thirty-six animals were divided into four groups of 9 animals per group: group I (Control); group II (3.5 mg/kg CdCl2); group III (100 mg/kg ICE + CdCl2); and group IV (250 mg/kg ICE + CdCl2). Animals were pretreated with 100 and 250 mg/kg ICE before co-administration with cadmium chloride. Results CdCl2 treatment caused a significant increase in acetylcholineesterase activity, lipid peroxidation, beta-amyloid aggregation, caspase 3 and 9, p53, and glutamate concentration. In addition, CdCl2 caused a significant decrease in catalase activity, superoxide dismutase, glutathione-S-transferase, Na+/K+ ATPase, and glutamate dehydrogenase. ICE was able to reduce the neuronal damaging effect of CdCl2 by acting as an antioxidant, antiapoptotic, anticholinesterase, and antiexcitotoxicity. Conclusions Our findings show that Ipomoea cairica leaf can be developed and included in the natural product in the prevention of neurodegenerative diseases.