Background: Health-care professionals across the globe are obligated to report adverse drug reactions (ADRs). The knowledge of ADRs and attitude of health-care professionals toward ADRs reporting is vital for patient safety. This study intends to investigate the knowledge of ADRs and attitude of health-care professionals toward ADRs reporting. Materials and Methods: A cross-sectional study using an anonymous questionnaire was conducted over a period of 3 months (September 2016 to November 2016) at King Saud Medical City, Riyadh, Saudi Arabia. This study included 399 questionnaires submitted by health-care professionals. Results: A total of 399 questionnaires were submitted by health-care professionals, of which only 14.8% knew the term “ADR” and 55.1% of the respondents reported ADRs during their practice. A total of 93.8% of the respondents agreed that ADR reporting should be made mandatory for health-care professionals, and 94.5% agreed that it improves the patient safety. Conclusion: The findings generally indicate that health-care professionals in a tertiary care setting have low awareness regarding the term “ADR.” Lack of pharmacovigilance training, amount of workload, and legal liabilities are the main causes of underreporting. More than half of the respondents agreed that ADR reporting eventually improves patient safety.