Onion skins (OS) are a by-product of onion processing that causes both biological and environmental problems. Thus, OS could be used sustainably and as means of circular economy since they contain valuable bioactive compounds that can be used for the production of high-added-value products. This study aims to evaluate the potential antioxidant, antimicrobial, and anticancer properties of onion OS crude extracts. The extracts were prepared using different solvents (i.e., water, ethanol, and their mixtures) and evaluated for their total phenolic content and phytochemical composition, their antioxidant activity (using the DPPH radical scavenging assay, the ferric reducing antioxidant power (FRAP) assay, and the hydrogen peroxide scavenging assay), anti-inflammatory properties, as well as for their antimicrobial (against Listeria monocytogenes, Escherichia coli O157:H7, Bacillus cereus, Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhimurium, and Yersinia enterocolitica) and anticancer (against human breast cancer cells (MCF-7) and human glioblastoma cells (U-87 MG)) activity. The results revealed that the extracts contained a significant amount of phenolic compounds, ranging between 348.71 and 795.11 mg gallic acid equivalents per g of dry weight. The extracts showed promising cytotoxic effects (up to ~40%) against cancer cell lines, indicating their potential as a natural source of anticancer agents. Additionally, the extracts exhibited strong antioxidant and antimicrobial activity against the tested microorganisms. The findings of this study suggest that OS crude extracts could be a promising candidate for developing natural functional foods and pharmaceuticals. They could be used as natural alternatives for the prevention and treatment of various diseases caused by oxidative stress, microbial infections, or cancer since they are a valuable source of bioactive compounds that can be used for various applications such as food preservation, nutraceuticals, and pharmaceuticals.