Gastric ulcer is one of the major gastrointestinal disorders affecting people worldwide. Despite medical advances, management of gastric ulcer and its complications remains a challenge facing medicine nowadays. In addition, currently available medicines exhibit limited efficacy and several side effects. In the current study, the potential protective effects of chrysin -naturally occurring flavonoid – were tested against indomethacin-induced gastric ulcer model in rats. It was found that chrysin in both doses; 50 and 100 mg/kg were effective in promoting mucus secretion and preventing the rise in ulcer and lesion indices, acid production and histologic changes induced by indomethacin. During investigation of the possible underlying mechanisms, chrysin significantly attenuated indomethacin-induced oxidative injury and inflammatory response. Also, chrysin activated peroxisome proliferator activated receptor-γ (PPAR-γ) leading to a phenotypic switch from pro-inflammatory M1 macrophages to the anti-inflammatory M2 macrophages that evidenced by the upregulated mRNA expression levels of PPAR-γ and M2 marker genes (Arg-1 and CD206) and down regulation of M1 marker genes (IL-6 and CCL3). Furthermore, chrysin promoted angiogenesis via increasing expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and cluster of differentiation-31 (CD31). Collectively, these findings indicate that chrysin possesses a potential protective effect against indomethacin-induced gastric ulcer.