On the basis of Phoenix dactylifera L. seeds, the effect of acetone, ethanol, and water on total phenolic content (TPC), total flavonoid content (TFC), total anthocyanin content (TAC), and antibacterial activity against Listeria monocytogenes, Staphylococcus aureus, Salmonella enterica, and Escherichia coli was examined. Here, the augmented simplex-centroid mixture design was implemented. All the independent and response variables were fitted to linear, quadratic, and special cubic models. The best results were obtained for the ternary mixtures, presenting TPC, TFC, TAC, L. monocytogenes, and anti-S. enterica activities; acetone–ethanol (53.32%–45.31%) with 25.46 mm for anti-S. aureus and acetone–water (50.19%–48.11%) with 24.56 mm for anti-E. coli activities were the best solvent mixtures. Optimal mixture predicted for highest phytochemical content corresponds to 22.39%, 37.37%, and 40.24% of acetone, ethanol, and water, respectively. While the optimal extraction mixture predicted for anti-foodborne pathogens activities contains 39.72% of acetone, 18.87% of ethanol, and 41.41% of water. Practical applications Recently, the tendency toward application of phytochemicals as safer antimicrobial agents has been increased. In this regard, Phoenix dactylifera L. seeds have high antibacterial activity against both gram-positive and gram-negative bacteria. This work demonstrated that solvent mixtures have been shown to extract significantly amounts of phenolic compounds with antibacterial activity. Thus, date palm seeds extracts can be used as natural and niche preservatives for the pharmacy, food, and cosmetics industries.