Objectives Evidence-based guidelines have the potential to reduce variation and increase prescribing quality. Identifying the key determinants to their uptake, using a theory-based approach, may assist in the design of successful interventions to increase their adoption into practice. This systematic review investigated barriers and facilitators identified using the Theoretical Domains Framework (TDF) to the implementation of prescribing guidelines. Methods Electronic databases (EMBASE, PubMed) were searched. Studies were included if they used the TDF to identify key determinants of guideline implementation. Only studies published in English were included. Key findings Of the 407 studies identified, 15 were included. A range of patient populations and therapeutic categories were represented. Multiple determinants were identified that affected guideline implementation, with similarities and differences identified across studies. Barriers to guideline adoption included time restriction, lack of awareness, guideline complexity, lack of clinical evidence, social influences and disagreement. Facilitators included peer influence, guideline simplicity, confidence and belief about the positive consequences derived from guideline adoption, for examples improved care and patient outcomes. Conclusions Multiple behavioural factors affect the adoption of prescribing guidelines. The results aided the understanding of factors that may be targeted to increase guideline compliance. However, barriers and facilitators can vary significantly in different environments; therefore, research that targets particular healthcare settings and patient populations may provide further evidence to increase the specificity and credibility of intervention strategies.