Background: One of the most prevalent types of peptic ulcers is stress-induced stomach ulceration. Various research have reported the biological and pharmacological potentialities of various Acacia saligna (AS) extracts, including their anti-inflammatory and antioxidant properties. Objective: This study aimed to illustrate Acacia saligna's underlying processes and gastroprotective effects in rats suffering from stress-induced stomach ulcers. Material and methods: Thirty male albino rats were split into: Control, ulcer, and ulcer + AS. Stomach ulcer index values, stomach PH, serum corticosterone, body weight change, gastric prostaglandin E2 (PGE2), gastric malondialdehyde (MDA), gastric superoxide dismutase (SOD), gastric TNF-α, gastric IL-6, and the expression of TLR4 and NF-κB genes were taken into consideration after two weeks. Additionally, stomach tissue was evaluated histopathologically and using NF κB immunohistochemistry. Results: While, the ulcer group had significantly higher serum corticosterone, gastric ulcer index values, gastric MDA, gastric TNF-α, gastric IL-6, and gastric gene expression of TLR4 and NF-kB, along with upregulation of NF-kB immunoreaction. They also showed significantly lower change in BW, gastric PH values, gastric SOD, and gastric PGE2 when compared to the control group. Stress-induced alterations in stomach tissue were significantly ameliorated by Acacia saligna. Conclusion: Through the downregulation of the TLR4/NF-kB signaling pathway and the presence of anti-inflammatory and antioxidant properties, Acacia saligna provides gastroprotective advantages to rats with stress-induced stomach ulcers.