AbstractA substantial global health burden is associated with neurotoxicity caused by lead (Pb) exposure and the common mechanism of this toxicity is mainly via oxidative damage. Curcumin has remarkable pharmacological activities but remains clinically constrained due to its poor bioavailability when orally administered. Currently, cockle shell‐derived calcium carbonate nanoparticle (CSCaCO3NP) is gaining more acceptance in nanomedicine as a nanocarrier to various therapeutics. This study aimed at investigating the ameliorative effect of curcumin‐loaded CSCaCO3NP (Cur‐CSCaCO3NP) on lead‐induced neurotoxicity in rats. A total of 36 male Sprague–Dawley rats were randomly assigned into five groups. Each group consists of 6 rats apart from the control group which consists of 12 rats. During the 4 weeks induction phase, all rats received a flat dose of 50 mg/kg of lead while the control group received normal saline. The treatment phase lasted for 4 weeks, and all rats received various doses of treatments as follows: group C (Cur 100) received 100 mg/kg of curcumin, group D (Cur‐CSCaCO3NP 50) received 50 mg/kg of Cur‐CSCaCO3NP, and group E (Cur‐CSCaCO3NP 100) received 100 mg/kg of Cur‐CSCaCO3NP. The motor function test was carried out using the horizontal bar method. The cerebral and cerebellar oxidative biomarker levels were estimated using ELISA and enzyme assay kits. Lead‐administered rats revealed a significant decrease in motor scores and SOD activities with a resultant increase in MDA levels. Furthermore, marked cellular death of the cerebral and cerebellar cortex was observed. Conversely, treatment with Cur‐CSCaCO3NP demonstrated enhanced ameliorative effects when compared with free curcumin treatment by significantly reversing the aforementioned alterations caused by lead. Thus, CSCaCO3NP enhanced the efficacy of curcumin by ameliorating the lead‐induced neurotoxicity via enhanced attenuation of oxidative stress.