Betel nut consumption has significant implications for the public health globally, as the wide-spread habit of Areca chewing throughout Asia and the Pacific is associated with a high prevalence of oral carcinoma and other diseases. Despite a clear causal association of betel nut chewing and oral mucosal diseases, the biological mechanisms that link Areca nut-contained molecules, inflammation and cancer remain underexplored. In this study we show that the whole Areca nut extract (ANE) is capable of mobilizing Ca2+ in various immune cell lines. Interestingly, none of the four major alkaloids or a range of other known constituents of Areca nut were able to induce such Ca2+ signals, suggesting that the active components might represent novel or so far unappreciated chemical structures. The separation of ANE into aqueous and organic fractions has further revealed that the calcium-mobilizing molecules are exclusively present in the aqueous extract. In addition, we found that these calcium signals are associated with the activation of several immune cell lines as shown by the release of pro-inflammatory cytokines and increased cell proliferation. These results indicate that calcium-mobilizing molecules present in the aqueous fraction of the Areca nut may critically contribute to the inflammatory disorders affecting betel nut chewers.