Several food additives are used to extend the shelf life of food, and delay or inhibit the growth of pathogenic microorganisms. Extracts of plants, particularly herbs and spices, are rich in essential oils and phenolic secondary metabolites and several possess antimicrobial activity. Some of these plant extracts are used in the aroma and flavor industry, and are classified as “generally regarded as safe” (GRAS). Oregano and cranberry extract mix provide a GRAS-type phytochemical source with the potential to develop a natural and effective antimicrobial strategy against Vibrio parahaemolyticus. Different ratios of extract mixtures were optimized from oregano and cranberry, and evaluated for antimicrobial activity in laboratory medium and seafood products. The results indicated that the antimicrobial activity was enhanced in response to extract mixtures than individual extracts of each species. The efficacy was further improved by combination with lactic acid, which is also considered GRAS. These results show the potential of plant extracts to be antimicrobial and, when combined with lactic acid, they can be used as a more effective multiple-barrier food preservation system. Such a synergistic ingredient approach can have wide implications for improvement of food safety.