Antibacterial agents with broad-spectrum antibacterial properties have always been in large demand. Lysozyme, a common and inexpensive protein, is widely used in food safety and biomedical applications for antibacterial purposes. However, many pathogens are lysozyme-resistant or insensitive. In this research, we investigated the antibacterial activities and mechanism of oligomers and amyloid fibrils formed from hen egg-white lysozyme (HEWL) against Staphylococcus aureus and Escherichia coli. The HEWL fibrils showed significantly enhanced antibacterial activity against both lysozyme-resistant S. aureus and lysozyme-insensitive E. coli. The HEWL oligomers, on the other hand, did not show an obvious improvement in antibacterial activity compared to native HEWL. Our results indicated that the fibrillation of HEWL can significantly enhance antibacterial activity against both S. aureus and E. coli. The natural and inexpensive HEWL amyloid fibrils can be potentially applied to antimicrobial food packaging, animal feed, antibiotic replacement, etc.