Under-utilized, ethnic, or traditional plant-based foods, food ingredients, or processed plant by-products have dual functional food safety and health protective benefits due to their rich phytochemical profile. Pre- and post-harvest strategies can enhance the phytochemical content in plant-based foods and by-products with an improvement in the overall food safety and health protective benefits. Based on this rationale, the food safety relevant antimicrobial properties of amla, kokum, clove, garlic, grape, flaxseed, emmer wheat and corn distillers dried grain with solubles (DDGS) were selectively screened for in vitro antimicrobial activity against common food borne pathogens Salmonella, Listeria, Escherichia coli and one human gut pathogen Helicobacter pylori. Additionally, the health protective benefits such as antioxidant, anti-hyperglycemic, anti-hypertensive, and prebiotic activity were also investigated using in vitro assay models. Pre-harvest (ozone treatment) and post-harvest (milling, fermentation, extraction, synergy) strategies were also utilized to improve the phytochemical-linked functionality of these plant-based foods and plant by-product. Amla, kokum, clove, and garlic displayed high antimicrobial activity against most of the Salmonella, Listeria, and E. coli serovars tested, and the antimicrobial activity was specific for the bacterial strain. Integration of amla and kokum in grape juice further enhanced the antimicrobial, anti-hyperglycemic, and anti-hypertensive activity of the grape juice. Pre-harvest ozone treatment of white and red grape cultivars resulted in improved TSP content and anti-hyperglycemic relevant α-amylase inhibitory activity. High phenolic-linked antioxidant activity was found in aqueous extracts of milled flaxseeds, while flax lignan had high anti-hypertensive property. Emmer wheat with hull had highest TSP content, antioxidant and antihyperglycemic activity (before and after milling) when compared to commercial wheat cultivars. Furthermore, extracts of Emmer fermented with lactic acid bacteria (LAB) showed an altered phenolic profile with mild antimicrobial activity against H. pylori. Extracts of corn DDGS fermented with LAB showed an altered phenolic profile and the antimicrobial activity against H. pylori was attributed a culture isolated from corn DDGS which was later identified as Bacillus amyloliquefaciens. These results indicate that screening and pre- or post-harvest processing strategies are an effective approach to improve the phytochemical-linked food safety and human health protective benefits of underutilized and common plant-based foods and plant by-product.