Bioinspired polypeptoids show great potential in many applications. Here, we report a convenient approach to synthesize a novel type of polypeptoid containing both sulfonium and oligo(ethylene glycol) (OEG) moieties by ring-opening polymerization (ROP) and a post-modification strategy. Three types of epoxides with (OEG)_n (n = 1–3) groups are involved to offer various functionalities. The obtained polypeptoid sulfonium salts show positive ζ potential, irrespective of the solution pH and the degree of polymerization (DP). We demonstrate that the polypeptoids exhibit excellent antibacterial activity against Staphylococcus aureus (S. aureus) with MIC (minimal inhibitory concentration) in the range of 3.9–7.8 μg mL⁻¹. In addition, the polypeptoids have a low hemolysis property and good in vitro biocompatibility. Remarkably, the as-prepared polypeptoids show rapid and potent antibacterial activity within 5 min. These features suggest that the obtained polypeptoids offer great potential for antimicrobial agents.