Many companies have used simulation techniques to improve their operations and generate process improvements for many years. Six Sigma has been developed as a disciplined approach and has introduced an alternative way of thinking about product or process improvement. The concept of combining the advantages of simulation techniques and Six Sigma's methodology has recently led companies and academics to investigate and implement this strategy. The Six Sigma method, composed by the Define, Measure, Analyze, Improve and Control stages, is a problem-solving method. However, it also identifies problems for which the approach may be ineffective. The objective of this study is to improve and control processes, reduce non-value-added activities and support decision-making by using Six Sigma's methodology alongside AnyLogic; using agent-based, discrete event, and system dynamics models. Moreover, the paper explores a multi-method simulation as a guided tool to assist organizations with the decision to implement a Six Sigma approach and pinpoints the strategies to be adjusted and monitor the process' parameters to be improved as well as reduce bottlenecks and weaknesses in the entire process by setting up management guidelines of such complex and dynamic process. This ensures that existing systems and proposed improvements account for any short and long-term outcomes. This paper begins with an overview of Six Sigma, followed by a description and the benefits of using the AnyLogic simulation package for implementing this methodology. This paper also shows the fundamental relationships between the Six Sigma methodology and AnyLogic simulation displaying a framework in which they can be integrated and a business case where this framework is used. The improvement and the strengths from this combination between Six Sigma and simulations are represented as preferable and capable enhancements to Six Sigma to deal with defects in many aspects.