The cultivation of the Mediterranean mussel, Mytilus galloprovincialis Lamarck, 1819, has been tested in an innovative Integrated Multitrophic Aquaculture system (IMTA) in the Mar Grande of Taranto, as part of the EU-funded Remedialife project. This farming method could solve several problems including the low growth rate in mesotrophic environments while reducing the environmental impact of fish mariculture. Three productive cycles have been carried out. The first (2018–2019, traditional experiment) was conducted in three long lines around six cages of the fish farm in order to evaluate total mussel production under the innovative IMTA system and quality for human consumption by analyzing the concentration of culturable heterotrophic bacteria, total and fecal coliforms, Escherichia coli and Salmonella spp. in mussel tissues. In addition, 17 polycyclic aromatic hydrocarbons (PAHs), including 16 EPA priority compounds and seven polychlorinated biphenyls (PCBs), which are indicators of PCB contamination in the environment, were analyzed using gas chromatography in conjunction with a mass spectrometer. The second cycle (2020–2021, horizontal distance experiment) aimed to test the influence of fish cages on mussel growth by placing mussels near and far from the fish cages. The third cycle (2021–2022, vertical distance experiment) aimed to overcome the phenomenon of “heat waves” that can occur in the Mar Grande of Taranto during summer by testing the growth performance of mussels at two different depths (1 and 12 m). The following parameters were measured: Shell Length, L (mm); Shell Dry Weight, SDW (g); Flesh Dry Weight, FDW (g); Condition Index, IC = FDW/SDW. The results showed that the best growth performance was obtained near the fish cages and at a depth of 12 m. Moreover, the indicators of microbial contamination and concentrations of chemical compounds analyzed in mussel tissues cultured under the innovative IMTA system were in compliance with the reference values of European regulations.