Increasing evidence indicates that pancreatic stellate cells (PSCs) are responsible for the stromal reaction in pancreatic ductal adenocarcinoma (PDAC). The interaction between activated PSCs and PDAC cells and the resultant stromal reaction facilitate cancer progression. Previous findings suggested that cyclooxygenase‑2 (COX‑2) may have a profound role in regulating the proliferation and activation of PSCs in response to pancreatic cancer. Indometacin, a well‑known anti‑inflammatory drug and a non‑selective inhibitor of COX‑2, has been shown to exert anticancer effects in various types of cancer, including PDAC. However, whether indometacin affects PSC activation remains unclear. Using RT‑qPCR and western blot analysis, we determined that COX‑2 expression was elevated in tandem with the activation of PSCs. Treatment with indometacin suppressed the viability and the migration ability of PSCs in a dose‑dependent manner. In addition, the immunoblotting and immunofluorescence results showed that α‑SMA expression was markedly decreased by indometacin. A further study indicated that COX‑2 expression was decreased in PSCs after indometacin intervention. In conclusion, these data indicate that indometacin serves as an effective drug against PSC activation via the targeting of COX-2.