The global pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 661 million infections and over 6.6 million deaths worldwide since its inception in 2019. There is an urgent need for safe and effective antiviral solutions, especially those with rapid inactivation kinetics, to help prevent viral transmissions. In this study, we report the design and synthesis of amphiphilic sulfonated polycarbonates and investigate the effect of polycarbonate compositions on their antiviral activity. A polycarbonate with an optimal balance of the hydrophilic anionic sulfonate (∼30%) and the hydrophobic n-butyl (∼70%) pendent groups inactivates various types of coronaviruses in solution, including huCoV-OC43, ancestral wild-type SARS-CoV-2, and the delta variant, within seconds, while exhibiting low cytotoxicity to mammalian cells (i.e., Vero E6) at the virucidal concentration. This amphiphilic sulfonated polycarbonate may be a promising solution to inactivate viruses as sprays for prevention of viral infection.