Laportea aestuans (Urticaceae) plant is widely distributed in tropical rain forests and used as remedial agent for various diseases in Nigeria by herbal practitioners. Ethanol consumption is one of the common causes of gastric ulcer due to excessive generation of reactive oxygen species and erosion of gastric mucosal layer. This study investigated the cytoprotective effect of pretreatment with methanol extract of Laportea aestuans (MELA) for 7 days on ethanol-induced gastric ulcer in male Wistar rats using cimetidine as a standard drug. Ulcerogenic parameters, oxidative damage, inflammatory and apoptotic markers were evaluated. MELA showed a significant dose-dependent (p < 0.01) decrease in ulcer score (US), ulcer index (UI) and peptic activity with an increase in mucus content and percentage inhibition compared to the ethanol group. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), Glutathione S-transferase (GST) and level of reduced glutathione (GSH) were also increased with concomitant decrease in malondialdehyde (MDA) level in MELA treated rats.  Serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and activities of cytochrome c (Cyt c), caspases-3 and -9 (CASPS-3 and -9) were also reduced by administration of MELA. Taking together, this study shows that MELA protected the gastric mucosal against the assault induced by ethanol via upregulation of the antioxidant system, and downregulation of inflammatory and apoptotic processes. HIGHLIGHTS Oral administration of ethanol to Wistar rats induced gastric ulceration Oral administration of ethanol to Wistar rats caused ulcer by generation of ROS, inflammation and induce apoptosis Pretreatment of rats with methanol extract of Laportea aestuans (MELA) preserved the gastric mucosal integrityby boosting antioxidant defence system and inhibiting inflammatory and apoptotic processes GRAPHICAL ABSTRACT