There is a growing interest in the use of anticariogenic and antimicrobial agents to prevent demineralization and promote remineralization of dental enamel for the prevention of oral diseases. The purpose of this study was to develop a novel chewing-system containing as Casein-Phosphopeptides-Amorphous-Calcium-Phosphate (CPP-ACP) as Quercetin (Qt) and evaluate their release using in vitro and in vivo experiments. In vitro and in vivo experimental protocols were designed to test the percentages of Ca from CPP-ACP and Qt released with time and their delivery rate from a chewing gum. The in vitro experiments were performed using a specifically designed chewing apparatus to test the release of Ca and Qt in artificial saliva in function of chewed time, while the in vivo experiments required a chew-out method with volunteers and the residual CPP-ACP and Qt present in the chewed gums was analyzed. This study demonstrated that both CPP-ACP'Ca and Qt were released during chewing although CPP-ACP'Ca was released from the chewing gum in a slower and more controlled manner than Qt. They were also both effectively retained in the oral cavity for all the investigated chewing time and according to their monitored release concentrations they were able to serve as a novel antiplaque agent. This research concludes that both drugs were efficiently released during the mastication process to fully exploit their anti-carious activity.