Milk is not only a source of nutrients, but also contains exosomes (Exo) that can serve as a vehicle for drug delivery. Here, we obtained bovine milk Exo using three efficient methods, demonstrating high quality for commercial production. The optimized Exo displayed a size of 105.2 nm and an entrapment efficiency of 88.4 %. The Exo has been functionalized with a combination therapy comprising isobavachalcone (IS) and polymyxin B (PB), referred to as IP-Exo. The antibacterial efficacy of IP-Exo was significantly enhanced, enabling the elimination of 99 % of multidrug-resistant (MDR) bacterial pathogens in 4 h. Furthermore, scanning electron microscopy images demonstrated that the drug combination led to the complete dismantling of the bacterial structure. IP-Exo showed nearly 100 % microbial inhibition in fresh orange juice and accelerated wound healing in mouse models. Collectively, IP-Exo provides excellent potential for application within the food industry and animal husbandry as a defense against bacterial pathogens.