Indomethacin (IND) is an extensively used drug. However, it provokes aggressive ulcerogenic potential. Chamomile is a widely used as natural herb with a powerful antioxidant activity. This study aims to assess the effects of chamomile flowers extract (CFE) in IND induced peptic ulcer (PU). Fifty rats classified to five groups; control, ulcer, and pretreated groups with CFE (200 mg/kg), pretreated with ranitidine RAN (50 mg/kg), and pretreated with CFE+RAN for 14 days pre-ulcer induction. Pretreatment with CFE and/or RAN significantly decreased ulcer index, gastric acidity, pepsin activity, gastric oxidative stress biomarkers, serum anti-inflammatory cytokines, and histopathological changes induced by IND. The pretreated groups significantly elevated gastric enzyme antioxidant activity, mucin content and gastric mucosal prostaglandin E2 with comparison to IND group. Pretreatment with CFE+RAN displayed the most gastroprotective effects compared with pretreated with either CFE or RAN alone. Collectively, the antisecretory and cytoprotective effects of antioxidant and anti-inflammatory activities demonstrated by the CFE's gastroprotective action.