BACKGROUND: An adverse drug reaction (ADR) is a response to a medicine that is not intended and is harmful, and which occurs at normal dose levels for humans. Currently, there are no estimates of the population-based prevalence of ADRs in the Kingdom of Saudi Arabia (KSA). OBJECTIVE: The aims of this study were to (1) estimate the population-based prevalence of ADRs in KSA, (2) describe the ADRs experienced by survey respondents, and (3) investigate the level of awareness of the ADR reporting system. PATIENTS AND METHODS: This was a cross-sectional survey using stratified, population-based sampling conducted at a chain of community pharmacies. RESULTS: Analysis was conducted on 5228 surveys; 50.17% of respondents were males, and the mean age was 39 ± 15 years (min = 18, max = 98). The sample prevalence of ADRs was 23.45% (95% CI 22.30-24.60%, P < 0.001). The estimated population prevalence (after weighting) was 28.00% (26.10-30.00%). Gastrointestinal disorders were the most commonly reported ADRs (58.73%), followed by general disorders and administration site conditions (19.74%). The largest drug class that was reported to lead to ADRs was nonsteroidal anti-inflammatory drugs (NSAIDs) (11%). Over 19% of the respondents who experienced an ADR required medical intervention to control the suffering induced by the ADR. Of the respondents who experienced an ADR, 371 (30.26%) were aware of the ADR reporting system but only 53 (14.29%) said that they had filed a report in the system. CONCLUSIONS: Our study estimated that 28% of the population experienced an ADR over a 1-year period in KSA. Risk factors for ADR included certain chronic disease groups and the use of certain classes of medications. Regulatory authorities in KSA intend to conduct more research and deploy educational interventions to reduce ADR rates in KSA. This will hopefully occur in an international context that promotes the standardized measurement of ADRs in the community. A subset of findings from this report was presented in an oral presentation at the Saudi Food and Drug Authority (SFDA) Annual Conference, September 27, 2018. In addition, a subset of findings from this report were presented on a poster at the International Conference of Pharmacoepidemiology and Therapeutic Risk Management (ICPE), August 27, 2019.