Background: The clinical effectiveness of hypertonic saline (HS) in individuals with cystic fibrosis (CF) can be compromised by adverse effects. The objective of this study was to examine the efficacy of hyaluronic acid (HA) in mitigating these negative occurrences. Methods: A comprehensive review of the literature was carried out using three electronic databases: Medline, Cochrane Central, and Embase. This systematic review and meta-analysis investigate the efficacy of hypertonic saline (HS) with and without hyaluronic acid (HA) in treating cystic fibrosis. Primary outcomes include the incidence of cough, throat irritation, unpleasant taste, and changes in FEV1. Our findings suggest that adding HA to HS significantly reduces adverse effects and enhances patient tolerability, marking a potential improvement in cystic fibrosis therapy. Risk ratios (RRs) and mean differences (MDs) with 95% CI were used to present evaluations. The quality of RCTs was evaluated using the Cochrane Risk of Bias Tool (CRBT). The quality of the observational study was evaluated using the Newcastle–Ottawa Scale. Results: From the 1960 articles retrieved from the initial search, five relevant studies (n=236 patients) were included in the final analysis. Compared with patients only on HS, patients with HS and HA were significantly less likely to experience cough (RR: 0.45; 95% CI, 0.28–0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22–0.81, P=0.009), and unpleasant smell (RR: 0.43; 95% CI, 0.23–0.80, P=0.09). In addition, patients with HS with HA had significantly less forced expiratory volume (FEV1) (MD: −2.97; 95% CI, −3.79–−2.15, P=0.52), compared to patients only on HS. Patients on HA + HS had significantly lower rates of cough (RR: 0.45; 95% CI, 0.28–0.72, P=0.001), throat irritation (RR: 0.43; 95% CI, 0.22–0.81, P=0.009), and bad smell (RR: 0.43; 95% CI, 0.23–0.80, P=0.09) when compared to patients on HS alone. Furthermore, compared to patients solely on HS, patients with HS plus HA exhibited a substantially lower forced expiratory volume (FEV1) (MD: −2.97; 95% CI, −3.79 to −2.15, P=0.52) as well. Conclusion: For CF patients who need ongoing HS therapy and have a history of poor therapy tolerance, adding HA is beneficial.