The purpose of this research aims to critically understand the role of entrepreneurship and human resources (HR) in supporting sustainability-oriented innovation (SOI) in supply chain (SC) of food retailers in Jordan, in order to provide a novel conceptual framework. Attempting to overcome challenges generated from unsustainable business performance such as seeking to reduce harmful environmental and social influences while taking into consideration of economic aspects, SOI has gained attention quickly since it brings transformations to products, processes, practices and behavioral patterns. There has been little theoretical and empirical understanding of how SOI in the Supply Chain Management (SCM) can offer a potential framework to link innovation orientation and sustainable orientation. Prior research has also had overlaps amongst the key themes used by most of the theoretical perspectives to understand SOI in food SC. This research also provides managerial recommendations concerning the applicability of SOI in food SC. The phenomena of SOI was explored and explained from four theoretical perspectives: network, entrepreneurship, innovation and sustainability. The methodology of this research is qualitative. A systematic literature review was followed to critically evaluate previous research, which led to constructing an initial conceptual framework. A two-stage approach was applied. First stage, eight expert interviews of HR managers and academic researchers were conducted to refine the initial conceptual framework resulting in a proposed framework. Second stage, a multiple-case study, including 30 semi-structured interviews, 18 observations and secondary data from six case studies of retailers, was conducted in 2019. High- order key themes of the four perspectives (network, entrepreneurship, innovation and sustainability) were examined in each case, drawing on common literature-based terminology. Cross-case analysis techniques were then used in order to refine the proposed framework and a final conceptual framework was constructed. The empirical work was conducted based on the views of various managers in food retailers in Jordan. The findings revealed that the interaction between the theoretical perspectives (namely network, entrepreneurship, innovation and sustainability) is important, in order to holistically understand SOI in food SCM. The research identified three key stages of establishing, developing and implementing SOI which have important applicability in food SC. The research suggested that the focal actor, as a corporate entrepreneur, with the integration of the network perspective establishes SOI at the actor level, then develops SOI at their dyad level and later with their network level to help produce SOI. Finally, the focal actor implements SOI and efficiently practices it with the other actors in order to enhance innovation activities and sustainability performance in food SC. It was also found that HR plays an important role in SC of retailers as HR engage in SC practices and they create and engage in different strategies focused on sustainability. HR also plays an important role in motivating employees to achieve the goals. The contribution of this research to knowledge is theoretical and methodological contributions and managerial implications. The contributions to theory were provided to the SCM literature with a novel theoretical association, where SCM as a foundational perspective and the other four perspectives were incorporated to understand SOI as well as providing a holistic conceptual framework for SOI in food SC. The methodological contributions were provided, linking between data and theory, supporting an analytical generalization. The research provided empirical findings for the supply chain of retailers from the analysis of the actor, dyad and network levels. The research further developed validity, reliability and trustworthiness to enhance the research quality. The managerial implications were indicated for different level managers, particularly for focal actors in addition to their dyadic actors and across their network.