Invasive fungal infections, including meningitis, cause a high mortality rate due to few available antifungal drugs and frequently associated side effects and quick emergence of drug-resistant fungi. The restrictive permeability of the blood-brain barrier (BBB) further limits the efficacy of antifungal agents substantially in treating meningitis. Hereby, we design and synthesize guanidinium-functionalized poly(2-oxazoline)s by mimicking cell-penetrating peptides. The optimal polymer, PGMeOx10 bearing a methylene spacer arm, displays potent activities against the drug-resistant fungi and biofilm, negligible toxicity, and insusceptibility to antimicrobial resistance. Moreover, PGMeOx10 can break BBB retractions to exert promising antifungal functions in the brain. PGMeOx10 demonstrates potent in vivo antifungal therapeutic efficacy in mouse models including skin infection, systemic infections, and meningitis. PGMeOx10 effectively rescues infected mice and reduces fungal burden and inflammation in the brain. These results and the excellent biosafety of poly(2-oxazoline)s indicate the effectiveness and potential of our strategy to design promising antifungal agents in treating systemic infections and meningitis.