Emergence of multidrug-resistant bacteria is a major global concern. According to WHO, methicillin-resistant Staphylococcus aureus (MRSA) is a threatening pathogen resistant to a wide spectrum of antibiotics. Herein, to overcome drug resistance in MRSA, we successfully integrated traditional antibacterial methods but with a novel trick that included use of hen egg-white lysozyme's special aggregates generated by fibrillization. The minimum inhibitory concentration of oxacillin (Ox) for MRSA declined from 600 μM to <20 μM when using aggregates. Scanning and transition electron micrographs showed completely disrupted cells when treated with aggregated protein/Ox (20 μM). The assisting role of aggregates to induce antibiotic hypersensitivity was continuous and stable, but sub-inhibitory antibiotic concentration (20 μM) was required again after 8 h. Investigations regarding mechanism of antibiotic hypersensitivity revealed that aggregates were oligomers but not mature fibrils. Furthermore, reactive oxygen species levels rose significantly after treating bacteria with aggregated protein/Ox. Study of resistance mechanisms indicated that in response to wall structure alterations, mecA expression dropped significantly in the presence of aggregated protein/Ox (20 μM) relative to Ox (20 μM). This observation can be a breakthrough in finding alternatives where antibiotic dosage can be significantly reduced, thereby preventing emergence of new multidrug-resistant bacteria.