This study fills a crucial gap in the research on Micro, Small, and Medium Enterprises (MSMEs), with the main objective of proposing a framework to support the integration of Industry 4.0 (I4.0) and sustainability into the supply chains of MSMEs. This integration is accomplished by people, process, and technology (PPT) mechanisms, all while adopting the triple bottom line (TBL) perspective. A mixed-method approach was employed for this study, which included a scoping review of 147 publications, expert panels, focus groups, and a survey with 55 valid responses. The findings identified 32 key indicators linked to the primary barriers and enablers of I4.0 and sustainability integration (S-I4.0) in MSMEs’ supply chains. This study also highlighted the dominant barriers and enablers within the PPT mechanisms and TBL dimensions, and their causal relationships and influences. The results were synthesized into a novel S-I4.0 framework, separately applied to Micro and Small Enterprises (MSEs) and Medium Enterprises (MEs) due to company size-related variations. This study offers valuable insights for academics and provides practical guidelines to assist MSMEs in integrating I4.0 and sustainability into their supply chains. An important contribution concerns to the need to treat MSEs and MEs differently. These research results provide relevant and novel guidance for MSEs and MEs to accelerate the S-I4.0 adoption process, with an immediate impact on their supply chains.