This study examines the combinations of internal and external knowledge flows between R&D incumbents and start-ups in the context of open innovation. While there is a growing body of knowledge which has examined how, in a knowledge economy, a firm’s knowledge and innovation activities are closely linked, there is no systematic review available of the key antecedents, moderators, mediators, and outcomes of knowledge spillovers. We have conducted a multi-stage research to identify, through a systematic review of literature (61 research articles), the antecedents, outcomes, moderators, mediators and control variables. In the second stage, we performed content analysis of the selected articles to capture the major themes, theory perspectives, geographical contexts, and keyword occurrences. Finally, the findings of the previous two stages helped us to advance a nomological network that addresses the strength of relationship between the observable constructs that emerged from the review of literature. Our findings demonstrate how knowledge spillovers can help incumbent organizations and start-ups to achieve improved innovation capabilities, R&D capacity, competitive advantage, and creation of knowledge ecosystems leading to improved firm performance. Our study has important implications for practitioners and managers - it provides managers with important antecedents of knowledge spillover (knowledge capacities and knowledge types) which directly impacts the R&D intensity and digitalization driving open innovation. It also suggests that a mix of different types of external knowledge partners, in combination with internal R&D capabilities, may be crucial for understanding the role of open innovation models in emerging economies