Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), poses a severe threat to human health due to the limited efficacy of traditional antibiotics and the rapid emergence of drug resistance. Quaternary ammonium compounds (QACs) are promising antibacterial agents with a membrane-disruptive mechanism that is less prone to inducing resistance. Herein, a series of novel phthalazine-derived QACs (2a–2v) were designed, synthesized, and evaluated for their antibacterial activities.