The objective of this research was to analyse the gastroprotective effect of Cissus quadrangularis extract (CQE) along with its mechanism underlying the therapeutic action against the gastric mucosal damage induced by aspirin. In this study, we investigated the effect of CQE on the course of experimentally induced gastric ulcer by analyzing the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), microvascular permeability, activity of nitric oxide synthase-2 (NOS-2), mitochondrial antioxidants, lipid peroxidation and DNA damage. A significant increase in vascular permeability, NOS-2 activity, TNF-alpha, IL-1beta levels and oxidative damage were noted in aspirin administered rats. Pretreatment with CQE (500 mg/kg bw/day) by oral gavage for 7 days significantly attenuated these biochemical changes caused by aspirin in rats. Tissue damage was showed by decreased levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) and an associated rise in lipid peroxidation (LPO) in mitochondria, which were reversed by CQE. In addition, CQE prevents oxidative damage of DNA by reducing DNA fragmentation indicating its block on cell death. Ulcer protection in CQE treated rats was confirmed by histoarchitecture, which was comprised of reduced size of ulcer crater and restoration of mucosal epithelium. Thus, reduced neutrophil infiltration, antiapoptotic and antioxidant action have a pivotal role in the gastroprotective effect of CQE.