Computer-based simulation (CBS) is an interactive pedagogical training method that has seen increased interest, especially in recent years. There is some evidence that CBS in pharmacy education is not as widely adopted compared to other healthcare disciplines. Pharmacy education literature to date has not specifically discussed the potential barriers which may cause this uptake challenge. In this systematic narrative review, we attempted to explore and discuss potential barriers that may impact the integration of CBS in pharmacy practice education and provide our suggestions to overcome them. We searched five major databases and used the AACODS checklist for grey literature assessment. We identified 42 studies and four grey literature reports, published between 1 January 2000 and 31 August 2022, which met the inclusion criteria. Then, the specific approach of Braun and Clarke for thematic analysis was followed. The majority of the included articles were from Europe, North America, and Australasia. Although none of the included articles had a specific focus on barriers to implementation, thematic analysis was used to extract and discuss several potential barriers, such as resistance to change, cost, time, usability of software, meeting accreditation standards, motivating and engaging students, faculty experience, and curriculum constraints. Ad- dressing academic, process, and cultural barriers can be considered the first step in providing guidance for future implementation research for CBS in pharmacy education. The analysis suggests that to effectively overcome any possible barriers to implementing CBS, different stakeholders must engage in careful planning, collaboration, and investment in resources and training. The review indicates that additional research is required to offer evidence-based approach and strategies to prevent overwhelming or disengaging users from either learning or teaching process. It also guides further research into exploring potential barriers in different institutional cultures and regions.