The properties of small- and medium-sized enterprises (SMEs) make them one of the most important categories of enterprises for the economics of challenging world. SMEs, in most countries, are still enterprises with marketing and financial challenges. In addition, most of these challenges are related to their production and product characteristics. On the other hand, SMEs should fulfil the costumer’s demands. In order to reach these goals, SMEs must reach the highest level of production quality and quantity and successfully sustain them. Consequently, various manufacturing paradigms have been offered by an Industry 4.0 concept, which offers a variety of solutions to increase the productivity and enhance the performance of SMEs. It should be noted that implementation of these manufacturing paradigms for SMEs is quite difficult and sometimes risky for several reasons. Still, amidst all these difficulties and challenges, the benefits and idealism of the Industry 4.0 paradigms prevail. From productivity to market, it is difficult to deny that SMEs are frightened by the challenges they face and fleeing from the potential of overcoming them. This paper is an extended version of the research by Ghafoorpoor Yazdi et al. (2018) and conducts a hybrid methodology to satisfy the SMEs by validating and verifying any optimization idea before implementing the Industry 4.0 concept. To reach the study goals, an intelligent Material Handling System (MHS) with agent-based control architecture has been developed. The developed MHS has been utilized for auto parts distribution. The system performance has been evaluated, and some solutions have been provided to optimize the performance of system. To evaluate the target system’s performance, an analytical time study method has been utilized. The time study has an Overall Equipment Effectiveness (OEE) standard approach to identifying the matters that need to be resolved and optimized to increase system performance. The other part of the methodology is generating a simulation model of the real system by use of ARENA® software to evaluate the system’s performance before implementing the optimization idea and modifying the real system. Furthermore, as the sustainability strategies create many synergistic effects for SMEs, after evaluating the effects of the optimization ideas on OEE percentage, the influence of the OEE changes on manufacturing sustainability has been investigated. The results show that optimizing the OEE in SMEs with sustainability approaches can create competitive advantages, rather than simply focusing on reducing unsustainability.