Background: High consequence infectious disease (HCID) outbreaks are a threat to societies globally. Evidence-based clinical management guidelines (CMGs) are important tools for translating evidence into clinical practice. However, developing guidelines is resource-intensive and guidelines must remain responsive to new evidence while being accessible to clinicians. This review aims to identify factors that impact the implementation of HCID CMGs across different contexts during health emergencies. Methods: A systematic review. Four databases ( Ovid MEDLINE, Ovid Embase, Ovid Global Health, and Scopus) were searched until November 2021, complemented by a grey literature search conducted on November 2021. Studies that explored implementation of HCID guidelines were included, without language restriction. Two reviewers screened articles and extracted data. Data was analysed using qualitative inductive thematic analysis. Results: Of 12,512 records, 28 studies were included, with most (61%, 17/28) set in high-income countries. Three overarching themes impacting HCID CMG implementation were identified: 1) Development and characteristics of CMGs, 2) Organisational and logistical factors, and 3) Realities of Implementing guidelines. Key recommendations included engaging all relevant representatives in CMG development, including those in endemic countries; integrating mechanisms for regular updates; supporting implementation by ensuring access to necessary resources (e.g., equipment, pharmaceuticals), and training; and enabling intra- and inter-organisational collaboration and communication channels. Importantly, recognising the challenges faced by staff in implementing new guidance is crucial, as is understanding the impact of a supportive environment on the effective implementation of care during emergencies. Conclusion: These findings highlight the need to bridge the gap between HCID CMGs development and their real-world implementation amid health emergencies. The complex factors impacting effective implementation should be addressed beginning at the development stage, with training focused on implementation during inter-epidemic times, and ongoing implementation monitored during outbreaks. Further research to guide implementation frameworks are recommended.