The present study was undertaken to explore gastroprotective effects of trigonelline (TRG) and to determine the potential mechanisms involved in this action. In order to evaluate the gastroprotective efficiency of TRG, an indomethacin-induced ulcer model has been applied. Antioxidants, cytokines, adhesion markers and apoptosis levels have been analyzed for the biochemical mechanism involved in TRG activity. TRG (45 mg kg⁻¹) pretreated rats significantly inhibited gastric lesions by 81.71%. Indomethacin administration raises the levels of leukotriene B₄ (LTB₄), lipid peroxidation and myeloperoxidase (MPO) with the significant declines of prostaglandin E₂ (PGE₂), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px) levels. Conversely, TRG (45 mg kg⁻¹) pretreated animals showed significant rises in PGE₂ and antioxidant levels along with substantial reductions in LTB₄, lipid peroxidation and MPO levels. Indomethacin-induced rats also exhibited considerable increases of pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels and decreases of anti-inflammatory cytokines such as interleukin-10 (IL-10) and interleukin-4 (IL-4), but these imbalances were normalized through treatment of TRG. The protective activity of TRG against indomethacin-induced gastric ulcer has been ascribed to three important mechanisms: (1) anti-inflammatory; (2) antioxidant; (3) anti-apoptotic pathways.