Foodborne illnesses due to the consumption of contaminated food are on the rise in recent years. Since contamination can occur anywhere during the production chain, appropriate control measures are needed to reduce the microbial load post-harvest. Current consumers prefer natural ingredients and processes over chemical or synthetic additives, since they are aware of the health risks that could arise from using synthetic ingredients. Current consumers also want healthy and safe foods with good taste, freshness, nutrition, as well as ease of use. Hence, to meet consumer preferences, the food industry is seeking natural options in food production. To maintain good taste, freshness, nutrition and sensory attributes, multiple hurdle approach may be a good option for the industry. In multiple hurdle approach, several interventions are combined to produce safe food with good nutrition, freshness and other sensory attributes. Plant-based compounds are potential candidates to include in the multiple hurdle approach, since these are well known for their antimicrobial and other health promoting properties. Many of these compounds are Generally Recognized as Safe (GRAS), are considered natural, food-compatible and hence, have the potential to be acceptable by the consumers. Plant-based compounds could be considered a viable option in organic production, since the organic food industries are limited in what they can use, based on the requirements of the USDA-National Organic Program. Research has shown that some plant-based compounds have potent antimicrobial activity in vitro and in/on foods. In this chapter, the potential for application of plant-based antimicrobials in multiple hurdle approach will be discussed. The antimicrobial activity of these compounds in vitro will be described. The application of plant-based antimicrobials for the post-harvest decontamination of fresh produce with emphasis on organic production will be covered. The use of these compounds to improve the microbial and toxicological safety of meat and poultry products will be explained. A unique way of applying some plant-based antimicrobials in foods via edible films will also be discussed. Plant-based compounds have the potential to decontaminate foods and improve their microbial safety, impart unique flavors and health-promoting properties to foods, reduce potentially carcinogenic compounds formed in grilled meats, and therefore, can help improve public health.