Abstract Background Pharmacovigilance (PV) demarcates all actions involving the detection and prevention of adverse drug reactions (ADR) for marketed drugs. However, ADRs are considerably underreported worldwide and continue to be a major concern to health care systems. This study aims to assess the knowledge, attitude, and perception of hospital pharmacists regarding medication safety concerning PV and ADRs across multiple tertiary care centers around Saudi Arabia. Methods This cross-sectional study was conducted between July 2019 and January 2020. Pharmacists working in the tertiary care centers of Riyadh City, Saudi Arabia were asked to participate in the study. A self-administered questionnaire was used to conduct this study, it consisted of: 63 questions out of which 19 questions were knowledge-based, 15 were attitude-based, and 29 were practice-based questions. Results A total of 350 pharmacists were distributed and 289 agreed to participate, giving a response rate of 82.6%. Most pharmacists were aware of the concept of VP and its functions (96.5%) and (87.2%), respectively. Moreover, 90% said that ADR can be preventable and non-preventable. However, the findings revealed inadequate knowledge about the overall PV field, where the majority of the pharmacists failed to correctly answer questions related to independent ADRs treatment, Augmented drug reaction, the international location of ADR, and the World Health Organization “online database” for reporting ADRs. Moreover, incomplete and/or wrong answers were recorded for questions that included single or multiple correct answers. Regarding the participants” attitude, 96.9% were interested in ADR reporting, agreeing that ADR is important to enable safe drug usage. Although a general positive attitude was recorded, pharmacists have stated that the three main barriers that hinder reporting ADRs are: unavailability of information about ADRs, lack of awareness about the need to report ADRs, and lack of time. Concerning practice, 69.2% said they received training in ADRs reporting, and 70% have reported ADRs more than once a week. Conclusion Surveyed pharmacists from Riyadh hospitals showed narrow knowledge of the PV field. However, a positive attitude and satisfactory practice was observed among pharmacists. These findings warrant the need for educational programs and an encouraging environment for ADR reporting to increase ADR reporting rates and support PV activities in Saudi Arabia.