Background: Antiplatelet agents (APL) are medications used to decrease the aggregation or adhesion of the platelets. Thereby, this study aimed to determine the gastrointestinal (GI) side effects of antiplatelets (aspirin and clopidogrel), demography of patients at risk, the percent of discontinuation of antiplatelets due to GI side effects and the effect of prophylactic therapy, in Medina, Saudi Arabia. Methodology: A cross-sectional study was done among 423 patients who attended the Cardiac Center at Al-Medina region, Saudi Arabia. A predesigned questionnaire was used to document the demographic data and use of aspirin or clopidogrel and their side effects. Results: The majority of the participants took APL as prevention of blood clots and its associated cardiac diseases. The overall prevalence of GI side effects of APL was 22%. The most common side effect was epigastric pain (17.40%), followed by heartburn (14.60%), nausea (11.08%), and the least were melena (2.80%) and hematemesis (1.80%). People on dual APL therapy experienced higher side effects in comparison to single drug that was 19.2%, which is a considerable percentage of discontinuation of APL due to its side effects, and 66.7% participants got a prophylactic proton pump inhibitor. Conclusion: The study calls for the provision of communication between the cardiologist, gastroenterologist, and the family physician to compare the benefits and risk of antiplatelets for each patient depending on their age, gender and previous health status.