To ensure business continuity in the post-COVID-19 era, decision-makers should reconfigure their traditional supply chain (SC) networks, assisted by the development and implementation of cutting-edge technologies. Recently, Industry 5.0 (I5.0) has gained increasing attention as a paradigm offering salient features for the creation of resilient and inclusive operations by ensuring long-standing SC sustainability. However, there has been insufficient analysis of the challenges of implementing I5.0 in SCs. Therefore, this study aims to understand the challenges of implementing I5.0 when managing the impact of SC disruptions due to the COVID-19 pandemic in an emerging economy. Both qualitative and quantitative methods were used for this research. First, the challenges to I5.0 implementation were identified through a literature review and experts’ feedback. Those challenges were examined and prioritised using the Best-Worst Method (BWM). Second, the contextual relationships amongst these challenges were analysed using interpretive structural modelling (ISM) with cross-impact matrix multiplication applied to classification (MICMAC) analysis. Findings showed that to adopt I5.0 initiatives successfully in order to manage the post-COVID-19 impact on SC sustainability, the active involvement of senior managers is required in the execution process. Findings also showed that financial support and funding (e.g., tax reduction, short loans, etc.) from investors and the government play a pivotal role in enabling sustainability in SCs. Finally, the challenges were classified using MICMAC analysis to provide valuable insights for managing future disruptions. This study is expected to help managers and decision-makers successfully overcome the challenges of implementing I5.0 in SCs and thus improve SC sustainability.