Introduction <p>To compare the efficacy and safety of a low-viscosity 0.3% hyaluronic acid (HA) ophthalmic solution with those of a comparator 0.3% HA formulation in patients with dry eye disease (DED).</p> Methods <p>In this double-blind, randomized, multicenter, noninferiority clinical trial, patients with mild-to-moderate DED were allocated at a 1:1 ratio to receive either low-viscosity or comparator 0.3% HA eye drops. Participants instilled the assigned study medications 5–6 times daily for 12&#xa0;weeks, and a follow-up evaluation was conducted 1 week after the final instillation. The primary end point was the mean change in the corneal fluorescein staining (CFS) score from baseline to week 12. Secondary outcomes included the conjunctival staining score, tear break-up time (TBUT), nonanesthetized Schirmer test results, ocular surface disease index (OSDI) score, and ocular soreness.</p> Results <p>A total of 292 participants were included in the full analysis set. The change in CFS score at week 12 (−0.03; 95% CI −0.1873 to 0.1346) met the predefined noninferiority margin. Compared with the baseline parameters, both formulations significantly improved all ocular surface parameters except ocular soreness score (all <i>P</i> &lt; 0.01). No significant between-group differences were observed across all secondary outcomes. Notably, blurred vision immediately after instillation was significantly less frequent in the low-viscosity HA group at all time points (<i>P</i> &lt; 0.01).</p> Conclusions <p>Compared with the comparator 0.3% HA formulation, the low-viscosity 0.3% HA formulation demonstrated comparable therapeutic benefits while reducing the incidence of viscosity-related adverse events. These findings indicated that the low-viscosity 0.3% HA ophthalmic solution may serve as a clinically meaningful alternative for patients with mild-to-moderate DED.</p> Trial Registration <p>ClinicalTrials.gov identifier NCT06388070.</p>