Background: Calotropis procera (Aiton) (Apocynaceae) is a traditional Indian medicinal plant and used in folk medicine for the past decade for the treatment of gastrointestinal disorders. Therefore the current investigation was undertaken to explore the gastroprotective effect of C. procera (Aiton) leaves extract using pylorus ligation-induced gastric ulcer in rats. Methods: The crude powder material was successively extracted with different solvents and concentrated at reduced pressure in a rotary evaporator. The current investigation was carried out by a pylorus ligation-induced gastric ulcer model in rats. Omeprazole, 20 mg/kg and 100, 250, and 500 mg/kg ethanol extract of C. procera (Aiton) leaves were administered orally for 15 consecutive days, on the last day six hours after pylorus ligation animals were sacrificed and the amount of gastric juice, pH, total and free acidity, ulcer index, and pro-inflammatory cytokines along with antioxidant parameters and total protein were also studied. Results: Pretreatment of C. procera (Aiton) leaf extract at the doses 250 and 500 mg/kg, significantly (p < 0.001) decrease the volume of gastric juice, free and total acidity as well as gastric lesions, and secretion of pro-inflammatory cytokine. On the other hand, the pH of gastric juice, mucin content, and total protein was also significantly decreased. Moreover, pretreatment of C. procera (Aiton) significantly (p < 0.001) boost the enzymatic activity and level of different antioxidant markers and attenuated the pylorus ligation-induced level of MDA (p < 0.05) in experimental animals. Conclusion: From this study, it is concluded that the ethanol leaf extract of C. procera (Aiton) extract possess considerable antiulcer and antioxidant potential. For further research findings, it is necessary to explore the mechanism of action for anti-ulcer activity.