Lean Six Sigma 4.0 (LSS 4.0) represents a transformative evolution of Lean Six Sigma, integrating Industry 4.0 technologies to drive smart manufacturing excellence. By leveraging Artificial Intelligence (AI), the Internet of Things (IoT), Digital Twins, and Big Data Analytics, LSS 4.0 enables realtime decision-making, predictive intelligence, and autonomous process optimization, enhancing efficiency, agility, and resilience in modern industrial environments. This paper introduces a conceptual framework for LSS 4.0, redefining the DMAIC (Define-Measure-Analyze-Improve-Control) methodology through IoT-driven process monitoring, AI-powered predictive analytics, and digital twin simulations. This transformation shifts manufacturing from reactive control to predictive and autonomous optimization, reducing variability, defects, and waste while maximizing productivity, resource efficiency, and sustainability. By leveraging data-driven decision-making, intelligent automation, and predictive maintenance, the framework enhances process reliability, prevents defects, and improves operational performance. Despite its advantages, LSS 4.0 presents challenges, including technological complexity, workforce upskilling, and organizational resistance. This study underscores the critical role of leadership-driven digital transformation, AI-augmented decision-making, and targeted skill development in fostering an innovation-driven manufacturing culture. Additionally, blockchain for secure supply chain traceability, augmented reality (AR) for enhanced humanmachine collaboration, and edge computing for decentralized intelligence are explored as key enablers of LSS 4.0’s full potential. Leadership commitment, cross-functional collaboration, and AI-driven Lean workflows are identified as essential success factors. Aligning digital transformation strategies with Lean principles and fostering a culture of continuous innovation is crucial for realizing LSS 4.0’s full benefits. Finally, this study highlights future research directions, emphasizing Industry 5.0 advancements such as human-centric automation, collaborative robotics, and sustainable smart manufacturing—key drivers in building adaptive, intelligent, and resilient industrial ecosystems.