Background: Acute poisoning is a common situation that occurs due to administrating harmful substances that impact the health with significant costs and increasing the rates of admission to emergency departments. Objectives: Assessing the knowledge of Saudi medical students toward the initial management of acute poisoning in Riyadh Region, Kingdom of Saudi Arabia (KSA). Methods: A cross-sectional study was done based on a questionnaire sheet conducted at Riyadh region in KSA from August to October 2017 among medical students. Results: Most of the subjects were at the seventh semester (69.7%), followed by 23.7% in the fifth academic semester and 13.7% at the sixth academic year. About 69.7% and 65.3% had previous exposure to first aid training and training in emergency setting. Most of the subjects had good knowledge about the definition of poisoning, early stages of acute poisoning, importance of maintaining airway, respiration and circulation as well as initial management using gastric lavage, char coal and antidotes. The level of knowledge was good among 77.3% of students but was insufficient among 22.7% of subjects. There were a significant association between higher educational semesters, training about first aid as well as training in emergency departments. Conclusion: The level of knowledge about initial management of acute poisoning was adequate among most of the students and was associated with training programs and experience in emergency departments. This study presented the importance of educational and training programs from the first year of the college to increase the knowledge and practice to save more lives.