Background: Decentralization and task-shifting of hepatitis C virus (HCV) infection testing and management from specialty services to primary care is vital to achieve global and Canadian HCV elimination targets since direct-acting antiviral therapy revolutionized HCV management. Primary care providers are instrumental in enabling more accessible and sustainable community-based HCV management. Understanding primary care providers' experiences and beliefs on provision of HCV treatment in primary care is vital to optimize primary care-directed HCV treatment. Purpose: We aimed to use best practices from implementation science to determine the key factors influencing primary care physicians' provision of HCV treatment and to synthesize the published evidence on the barriers and enablers to optimizing primary care-directed HCV treatment to inform future implementation interventions. Method: In Study 1, we conducted theory-informed interviews with family physicians practicing in Ontario, Canada to identify perceived barriers of and enablers to their provision of HCV treatment. The interviews and data analysis were guided by the Theoretical Domains Framework (TDF), which incorporates 33 theories of behaviour change into 14 domains to systematically identify cognitive, affective, social, and environmental influences on health behaviours. In Study 2, we conducted a systematic review of the barriers and facilitators to optimizing primary care-directed HCV treatment using the TDF as the organising framework. We characterized key determinants of primary care-directed HCV treatment by using the theoretical constructs, generating themes, and mapping themes to relevant TDF domains to identify potential targets for future implementation interventions. Results: We conducted semi-structured TDF-based interviews with 20 family physicians and found 'knowledge gap of HCV treatment guidelines', 'time and resource constraint and competing priorities in primary care', and 'clarity of primary care physicians' professional role in HCV treatment cascade' were the key barriers and enablers to provision of HCV treatment in primary care. The systematic review included 20 studies which suggested 'enabling environment', 'primary care capacity', and 'knowledge deficit in HCV treatment guidelines' were the key factors coded to 'Environmental context and resources', 'Social influences', 'Identity and social professional role', and 'Knowledge' as the most relevant TDF domains to influencing the optimization of primary care-directed HCV treatment. Conclusion: Our results provided practical insights into the barriers and enablers to better primary care-based HCV management. Future research will focus on developing implementation strategies to tackle the barriers and fortify the enablers to optimal HCV treatment in primary care.