PurposeThe primary aim of this article is to ascertain the modalities of leveraging Lean Six Sigma (LSS) for Industry 4.0 (I4.0) with special reference to the process industries. Moreover, it intends to determine the applicability of simulation-based LSS in the automation of the mineral water industry, with special emphasis on the robust design of the control system to improve productivity and performance.Design/methodology/approachThis study adopts the action research methodology, which is exploratory in nature along with the DMAIC (define-measure-analyze-improve-control) approach to systematically unearth the root causes and to develop robust solutions. The MATLAB simulation software and Minitab statistical software are effectively utilized to draw the inferences.FindingsThe root causes of critical to quality characteristic (CTQ) and variation in purity level of water are addressed through the simulation-based LSS approach. All the process parameters and noise parameters of the reverse osmosis (RO) process are optimized to reduce the errors and to improve the purity of the water. The project shows substantial improvement in the sigma rating from 1.14 to 3.88 due to data-based analysis and actions in the process. Eventually, this assists the management to realize an annual saving of 20% of its production and overhead costs. This study indicates that LSS can be applicable even in the advent of I4.0 by reinforcing the existing approach and embracing data analysis through simulation.Research limitations/implicationsThe limitation of this research is that the inference is drawn based on a single case study confined to process industry automation. Having said that, the methodology deployed, scientific information related to optimization, and technical base established can be generalized.Originality/valueThis article is the first of its kind in establishing the integration of simulation, LSS, and I4.0 with special reference to automation in the process industry. It also delineates the case study in a phase-wise manner to explore the applicability and relevance of LSS with I4.0. The study is archetype in enabling LSS to a new era, and can act as a benchmark document for academicians, researchers, and practitioners for further research and development.