Dry eye disease (DED) is a common ocular surface disorder. Esculin and digitalis possess anti-inflammatory and anti-oxidant properties, which may benefit patients with DED. This study aimed to assess the therapeutic efficacy of esculin and digitalis glycosides (EAD) eye drops, either alone or in combination with 0.3% sodium hyaluronate (SH) eye drops, in treating DED. In this randomized controlled trial, 78 participants with DED (78 eyes) were included and divided into three groups: Group A received 0.3% SH, Group B received EAD, and Group C received 0.3% SH combined with EAD eye drops for 4 weeks. The efficacy of the treatments was assessed at 2 and 4 weeks using the Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), Schirmer I test (SIt), and corneal fluorescein staining (CFS) as primary evaluation metrics. After 4 weeks of treatment, Group A showed a decrease in OSDI and an increase in SIT (p <
0.05). Group B showed a decrease in OSDI score (P <
0.05) and a significant improvement in SIt (P <
0.01). Group C demonstrated a significant increase in both TBUT and SIt values at the 2-week mark. Improvements were noted across all parameters, including OSDI score, TBUT, SIt, and CFS score after 4 weeks of treatment (P <
0.05). The total effective rate for participants in Group C was 88.46%, significantly higher than Group A's rate of 65.38% (P <
0.05). In conclusion, the combination of EAD eye drops with 0.3% SH eye drops proved more effective than either treatment alone.