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Background: Drug abuse is a worldwide issue affecting all human life aspects including health, social, economic, and security status. According to the United Nations Office on Drug and Crime reports, over 5% of adults used drugs at least once in the year 2015, and 29.5 million of them had consequences of inappropriate use of drugs. Information about severity of the problem in Saudi Arabia is limited, and therefore, a study was conducted among pharmacy staff to assess their knowledge, belief, and practice on drug misuse and abuse. Materials and Methods: A cross-sectional study was carried out in Eastern Province, Saudi Arabia. Pharmacy professionals with more than three months of experience were included in the study. A structured questionnaire was used to obtain participant's responses. Chi-square test was used to evaluate the association of sociodemographic factors with the participant's responses. Results: Ninety pharmacy professionals responded to this study. Overall 69 (76.7%) participants agreed that misuse and abuse are two different terms. Overall 48.9% (n = 44) of participants believed that the misuse or abuse of medications in Saudi Arabia is in an alarming situation. In addition, study showed different practices for patients who were suspected to be medication abusers. Conclusion: This study provided an initial picture about pharmacy staffs' knowledge and opinion regarding the misuse and abuse of medicines in Saudi Arabia. Participants' reactions and practices toward such behaviors were different and not consistent. Therefore, there should be a clear policy to define the role of the pharmacy staff toward the misuse and abuse of medication in Saudi Arabia.