Background <p>Fragmented healthcare systems hinder pharmacists’ access to comprehensive patient data, limiting their clinical role and posing health risks. Enhancing system interoperability and evaluating factors influencing pharmacists' readiness for technology-driven practice change is a crucial step.</p> Aim <p>This systematic review aimed to investigate the digital determinants of pharmacists’ readiness for technology-oriented practice change and interoperability.</p> Method <p>A systematic search of PubMed, Scopus, and Cochrane Library was conducted on August 7, 2023, with registration number INPLASY202380071. Search method was developed, and quality was assessed using the Boynton and Greenhalgh Quality Checklist (BGQC) and Critical Appraisal Skills Programme (CASP).</p> Results <p>The review included 13 studies, of which 7 (53.8%) included the study’s setting. Of the seven studies, most discussed the community pharmacy setting (n = 3, 23.1%), followed by hospital pharmacy (n = 1, 7.6%), and both settings (n = 3, 23.1%). The studies included several countries: the United Kingdom (UK), Canada, the United States of America (USA), Australia, India, Sweden, and Saudi Arabia. The studies discussed several medical health informatic technologies such as electronic health records and e-prescribing. The three most reported technology-related influencing factors were related to digital literacy and technology-oriented tailored training (n = 9, 69.2%), followed by technical system features (n = 6, 46.2%) and technology operations (n = 5, 38.5%). The overall readiness level for technology-related practice change was intermediate (n = 7, 53.8%), high (n = 3, 23.1%), and low (n = 3, 23.1%).</p> Conclusion <p>Digital literacy, tailored training, and system features are crucial for enhancing pharmacists’ readiness for technology adoption, highlighting the need for improved digital infrastructure and interoperability in clinical practice.</p>