Background: Grape agri-food wastes, such as skin, seeds, and other discarded by-products, contain phytochemical compounds that offer potential health benefits. Methods: This study aimed to investigate the polyphenol composition and bioactivities of different extracts obtained from grape marc and seeds, with the goal of exploring their potential for application as natural food additives. Results: Regardless of the extraction method used (dynamic maceration, ultrasound-assisted extraction (UAE), and microwave-assisted extraction (MAE)), all extracts exhibited relatively high concentrations of phenolic compounds. The chemical characterization of the extracts revealed the presence of specific compounds and chemical groups associated with each extraction methodology. Moreover, the extracts displayed satisfactory antioxidant activities, especially in inhibiting lipoperoxidation as assessed by the TBARS assay. Additionally, the extracts demonstrated effective inhibition against different strains of bacteria and fungi known as food contaminants. Taken together, these findings indicate that those extracts have the potential to be tested as natural antioxidants and preservatives with sustainable origins in food and beverage systems. Among the extraction methods evaluated, traditional maceration and UAE provided extracts with the highest antioxidant and antimicrobial activities. Conclusions: Our results suggest the opportunity to explore grape marc and seeds discarded by the winery industry in Portugal as natural sources of bioactive compounds, which could be employed as functional food ingredients or technological additives. The valorization of grape biowastes offers a promising strategy to reduce waste and harness their potential health benefits.