The optimization of production processes has always been one of the cornerstones for manufacturing companies, aimed to increase their productivity, minimizing the related costs. In the Industry 4.0 era, some innovative technologies, perceived as far away until a few years ago, have become reachable by everyone. The massive introduction of these technologies directly in the factories allows interconnecting the resources (machines and humans) and the entire production chain to be kept under control, thanks to the collection and the analyses of real production data, supporting the decision making process. This article aims to propose a methodological framework that, thanks to the use of Industrial Internet of Things—IoT devices, in particular the wearable sensors, and simulation tools, supports the analyses of production line performance parameters, by considering both experimental and numerical data, allowing a continuous monitoring of the line balancing and performance at varying of the production demand. A case study, regarding a manual task of a real manufacturing production line, is presented to demonstrate the applicability and the effectiveness of the proposed procedure.