There are increasing impacts and transformations in supply chains because of the integration of Industry 4.0 and sustainability (S-I4.0) in the context of micro, small, and medium-sized enterprises (MSMEs), given that the methods applied to large companies do not necessarily work for MSMEs. More recently, academics and professionals have devoted considerable and increasing attention to the subject due to the importance of investigating the topic to fill this gap. In this sense of integrating S-I4.0 in the supply chain of MSMEs, barriers act as obstacles, and enablers need to be enhanced. Furthermore, from the perspective of the triple bottom line (TBL), integration is carried out through mechanisms of people, processes, and technology (PPT). Within this context, this thesis aims to develop a Framework for Industry 4.0 and sustainability integration (S-I4.0) in the supply chains of Micro, Small, and Medium Enterprises (MSMEs). Towards achieving this goal, a mixed-method approach is adopted, with scope reviews, expert panels, focus groups, surveys, and multiple case studies (MCS), using fuzzy logic, in addition to the DEMATEL and ARAS methods. Eight barriers, eight facilitators, and their respective cause-effect relationships are the result of this study, in addition to the presentation of 32 key indicators, two for each of the barriers and enablers. Subsequently, these barriers and enablers have their dominance identified in the PPT and TBL axes, in addition to the mapping of causal and influence relationships, which allow the elaboration of four frameworks, two for MSEs and two for MEs separately for barriers and enablers. Finally, under the lens of Practice-Based View (PBV) and Dynamic Capabilities Theory (DCT), an MCS is carried out with six companies to apply these tools, mainly to create a practical guide on the journey to integrate S-I4.0 in the supply chains of MSMEs. This study makes fundamental contributions by proving the need to treat MPEs and MEs differently and offering valuable information and innovative tools for academics, managers, and practitioners by providing a practical guide to integrate S-I4.0 in the supply chains of MSMEs.