Background: Areca quid chewing increases the prevalence of periodontal diseases. Areca nut extract (ANE) inhibits the defensive functions of human polymorphonuclear leukocytes (PMNs). This in vitro study investigates the effects of ANE on the production of cyclooxygenase (COX)‐2 and the inflammatory mediator prostaglandin E 2 (PGE 2 ) by PMNs. Methods: The possible effects of ANE on the production of COX‐2 were examined using Western blotting analysis. The viability and production of PGE 2 of treated PMNs were determined using the propidium iodide staining method and the competition enzyme assay, respectively. The possible pathways involved were also examined using the COX‐2 inhibitor (NS398), the intracellular calcium chelator 1,2‐bis(2‐aminophenoxy)ethane‐N, N, N′, N′‐tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA‐AM), the p38 mitogen‐activated protein kinase (MAPK) inhibitor (SB203580), and the extracellular signal‐regulated protein kinase (ERK) inhibitor (U0126). The effects of ANE on the viability or PGE 2 production were statistically assessed using a one‐way analysis of variance and Tukey multiple‐comparison intervals with α = 0.05. Results: ANE significantly induced the production of PGE 2 in a time‐ and concentration‐dependent manner. This induction resulted from an increased expression of COX‐2. Moreover, the application of BAPTA‐AM, SB203580, and U0126 statistically significantly suppressed the induction of PGE 2 . Conclusions: ANE induced the production of PGE 2 . The activation of the intracellular calcium concentrations, p38 MAPK, and ERK may be involved in the inducing effects of ANE on PMNs. The findings suggest that areca nut chewing may induce an inflammatory response and affect the periodontal health of consumers.