Aim Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common condition that causes significant economic burden and reduced quality of life. Interactions between environment and nasal innate immune system contribute to the pathophysiology of CRSwNP. Nasal saline irrigation (NSI) is used as a first-line and post-surgical treatment following endoscopic sinus surgery. However, there are limited studies on the efficacy of different NSI formulations and their effect on nasal innate immunity. This randomised controlled trial evaluates the effects of isotonic (IsoSal) and low-sodium (LowNa) NSI on nasal innate immune proteins in patients with CRSwNP. Methodology Twenty-one participants with CRSwNP were recruited and randomly assigned to receive either IsoSal or LowNa NSI. Participants were blinded to their allocation. Nasal secretion samples were collected at baseline and after 14 days of daily NSI use. Samples were analysed using liquid chromatography and mass spectrometry to assess changes in protein concentrations with q-value <0.05 set as significant. Results A total of 3,850 proteins were identified in nasal secretions, several of which are known to play a role in nasal innate immunity. In the IsoSal group, 29 innate immune proteins showed significant changes after 14 days, with most decreasing in concentration, and 5 increasing in concentration. In the LowNa group, significant changes were observed in 11 innate immune proteins, with 9 increasing in concentration. Notably, lysozyme (a key antimicrobial protein) level showed greater increase in LowNa than in IsoSal group. Conclusion Regular use of NSI significantly influences the innate immune proteome in patients with CRSwNP. This study suggests that LowNa NSI greater enhances the production of nasal innate immune proteins compared to IsoSal NSI. This may provide greater therapeutic benefits to CRSwNP patients by strengthening their nasal mucosal barrier and enhancing antimicrobial potential.