(1) Background: Gastroduodenal perforation (GDP) is a life-threatening condition caused by a spontaneous or traumatic event. Treatment should be based on the mechanism of damage, timing, location, extent of the injury, and the patient’s clinical condition. We aimed to examine several etiologic factors associated with gastroduodenal perforation and to search for the best method(s) for its prevention and treatment. (2) Methods: We conducted extensive literature reviews by searching numerous studies obtained from PubMed, Science Direct, and Cochrane for the following keywords: gastroduodenal perforation, Helicobacter pylori, NSAIDs’ use, side effects of GDP, laparoscopy, and surgery. The primary outcome was the reported occurrence of GDP. (3) Results: Using keywords, 883 articles were identified. After applying the inclusion and exclusion criteria, 53 studies were eligible for the current analyses, with a total number of 34,692 gastroduodenal perforation cases. Even though the risk factors of gastroduodenal perforation are various, the prevalence of H. pylori among patients with perforation is considerably high. As technology develops, the treatment for gastric perforation will also improve, with laparoscopic surgery having a lower mortality and complication rate compared to open surgery for GDP treatment. (4) Conclusions: H. pylori infection plays the most significant role in GDP, more than NSAIDs, surgery, chemotherapy, or transplantation. Treatment of H. pylori infection is essential to decrease the prevalence of GDP and speed up its recovery. However, urgent cases require immediate intervention, such as laparoscopic or open surgery.