Background/Objectives: Ceragenins (CSAs) maintain strong antibacterial activity even in cystic fibrosis (CF) sputum. Ivacaftor (IVA), a CF transmembrane regulator modulator, provides significant clinical benefits in CF therapy. Based on these properties, we hypothesized that the combination of CSAs and IVA, due to their antibacterial and biofilm-penetrating abilities, may also be beneficial in the treatment of chronic rhinosinusitis (CRS), including CRS in CF patients. Notably, the physicochemical properties of biofilms in chronic rhinosinusitis (CRS) resemble those in CF sputum. Methods: We determined the minimal inhibitory and bactericidal concentrations (MIC and MBC) and the fractional inhibitory concentration index (FICI) for ceragenins (CSA-13, CSA-44, CSA-131), ivacaftor (IVA), selected conventional antibiotics, and their combinations against both reference and clinical strains. Bacterial viability within biofilms was also evaluated following exposure to these agents. Atomic force microscopy (AFM) was used to analyze the morphology and nanomechanical properties of Staphylococcus aureus and Pseudomonas aeruginosa. In addition, rheological measurements of Pseudomonas aeruginosa biofilms treated with CSAs combined with IVA were performed using a rotational rheometer. Results: The tested agents demonstrated anti-biofilm activity against bacterial strains associated with CRS development. IVA enhanced the anti-biofilm effects of both CSAs and tested antibiotics. CSAs exhibited low MIC and MBC values, confirming their efficacy against tested pathogens. AFM showed that CSA-44, IVA, vancomycin, and their combinations altered the nanomechanical properties of Pseudomonas aeruginosa and Staphylococcus aureus cells. Interestingly, the addition of IVA induced aggregation of S. aureus cells. CSAs reduced the stiffness of P. aeruginosa biofilms, and co-treatment with IVA resulted in a further decrease in biofilm stiffness. Conclusions: These findings indicate that ceragenins, particularly in combination with ivacaftor, represent a promising therapeutic strategy for challenging chronic infections caused by the studied bacteria. This supports further research aimed at developing new treatment methods for CRS.