<p>Blepharitis and meibomian gland dysfunction (MGD) commonly cause ocular surface symptoms, but comparative evidence for commonly used eyelid-cleansing strategies remains limited. We compared the 4-week efficacy of preformulated eyelid cleansing wipes, hypochlorous acid-assisted cleansing, and saline-assisted cleansing in adults with blepharitis-associated ocular surface disease. In this single-center, randomized, assessor-masked, parallel-group trial, adults aged 18–70 years were assigned to one of three cleansing interventions for 4 weeks. The primary endpoint was the baseline-adjusted Week 4 visual analog scale (VAS) score for the selected study eye in the full analysis set. Pairwise comparisons were performed only after a significant overall test, with Holm adjustment. Seventy-two participants were randomized; 64 were included in the full analysis set, and 59 had observed Week 4 VAS data. The overall between-group difference in baseline-adjusted Week 4 VAS was significant (P = 0.007). Adjusted mean Week 4 VAS values were 27.47 (95% CI, 22.18–32.76) in the wipe group, 33.16 (95% CI, 27.80–38.51) in the hypochlorous acid group, and 40.83 (95% CI, 34.93–46.72) in the saline group. The wipe group had lower Week 4 VAS than the saline group (adjusted difference, − 13.35; 95% CI, − 21.51 to − 5.20; Holm-adjusted P = 0.005). No other pairwise comparison remained significant. Between-group differences in Schirmer test result, corneal fluorescein staining, and MGD expressibility were interpreted as supportive secondary findings. In this single-center, assessor-masked randomized trial, preformulated eyelid cleansing wipes were associated with a lower baseline-adjusted Week 4 VAS symptom score than saline-assisted mechanical lid cleansing. Confirmatory superiority over hypochlorous acid was not established, and sign-based secondary findings should be interpreted as supportive. </p>