Stress is a typical body's natural defense to a generic physical or psychic change. A specific linking mechanism between ulcer onset and psycho-physical stress prolonged exposure has been reported. We decided to investigate the possible effects of Borago officinalis L. (Borago) in preventing physical (stress)-induced gastric ulcers in a rat model. Eighty male Sprague-Dawley rats were randomly divided into 16 groups, pretreated with a control solution, omeprazole (20 mg/kg), Borago methanolic extract (25, 50, 100, 250, and 500 mg/kg), Borago organic extract (50, 100, 250, and 500 mg/kg), Borago aqueous extract (5, 10, 20, 30, and 40 mg/kg), and D(-)-2-Amino-5-phosphonovaleric acid (AP5) (25 mg/kg) and kept in stressful conditions such as water immersion and restraint-induced stress ulcers. The animals were sacrificed and their stomach scored for the severity and the number of gastric ulcers. Methanolic extract (500 mg/kg) significantly reduced both ulcer parameters (*** p < 0.001 and ** p < 0.01, respectively). Aqueous and organic extract significantly decreased severity score at 5 and 10 mg/kg (** p < 0.01 and *** p < 0.001, respectively), and at 250 and 500 mg/kg (*** p < 0.001), respectively, while gastric ulcers' resulted number significantly reduced only at 10 mg/kg (* p < 0.05) and at 500 mg/kg (** p < 0.01), respectively. On the other hand, aqueous extract significantly increased the mucosal gastric content of cAMP (* p < 0.05) and NR2A and NR2B subunits (* p < 0.05 and ** p < 0.01, respectively) at 5 mg/kg. Organic extract showed also a significant cytotoxic effect at 500 and 1,000 mg/kg with a 3T3 cell viability reduction of 43.6% (** p < 0.01) and 92.1% (*** p < 0.001), respectively. Borago aqueous extract at 10 mg/kg could be considered as a potential protective agent against stress-induced ulcers, and it is reasonable to possibly ascribe such protective activity to a modulation of the NR2A and NR2B subunit expression.