In recent years, Industry 4.0 (I4.0) has been a recurrent theme in the literature on Lean Six Sigma (LSS), given the synergies that can arise from their combination. However, their joint implementation presents several challenges. In this article, a systematic literature review (SLR) of research on I4.0 and LSS integration was performed. This review involved five database platforms and included seventy-four articles providing state-of-the-art knowledge on the topic, focusing on the barriers to and enablers of integration. As a result, 20 integration barriers were identified, highlighting the high implementation cost, long learning curve, and technology incompatibility as the main barriers. Seventeen enablers were found to facilitate and guarantee implementation success, highlighting investment in IT infrastructure and employee training, stakeholder involvement, and top management support. In addition, the article discusses actions to facilitate I4.0 and LSS integration in practice, determined by connecting the identified enablers to their corresponding barriers. Finally, the SLR identifies several avenues for future research.