Cadmium (Cd), an environmental and industrial pollutant, affects the nervous system and consequential neurodegenerative disorders. Recently, we have shown that celastrol prevents Cd‐induced neuronal cell death partially by suppressing Akt/mTOR pathway. However, the underlying mechanism remains to be elucidated. Here, we show that celastrol attenuated Cd‐elevated intracellular‐free calcium ([Ca2+]i) level and apoptosis in neuronal cells. Celastrol prevented Cd‐induced neuronal apoptosis by inhibiting Akt‐mediated mTOR pathway, as inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced celastrol's prevention of Cd‐induced phosphorylation of S6K1/4E‐BP1 and cell apoptosis. Furthermore, chelating intracellular Ca2+ with BAPTA/AM or preventing [Ca2+]i elevation using EGTA potentiated celastrol's repression of Cd‐induced [Ca2+]i elevation and consequential activation of Akt/mTOR pathway and cell apoptosis. Moreover, celastrol blocked Cd‐elicited phosphorylation of CaMKII, and pretreatment with BAPTA/AM or EGTA enhanced celastrol's suppression of Cd‐increased phosphorylation of CaMKII in neuronal cells, implying that celastrol hinders [Ca2+]i‐mediated CaMKII phosphorylation. Inhibiting CaMKII with KN93 or silencing CaMKII attenuated Cd activation of Akt/mTOR pathway and cell apoptosis, and this was strengthened by celastrol. Taken together, these data demonstrate that celastrol attenuates Cd‐induced neuronal apoptosis via inhibiting Ca2+‐CaMKII‐dependent Akt/mTOR pathway. Our findings underscore that celastrol may act as a neuroprotective agent for the prevention of Cd‐induced neurodegenerative disorders. J. Cell. Physiol. 232: 2145–2157, 2017. © 2016 Wiley Periodicals, Inc. Celastrol prevents Cd‐induced elevation of [Ca2+]i, which results in inhibition of CaMKII phosphorylation. This leads to suppression of CaMKII‐dependent Akt/mTOR pathway, thereby preventing Cd‐induced apoptosis in neuronal cells.