Background Polyethylene covers are claimed to be useful in preventing ocular surface diseases (OSD); however, evidence of their clinical efficacy is limited. This clinical trial aimed to compare the use of polyethylene eye covers and artificial teardrops versus normal saline on the incidence and severity of OSD in comatose patients. Methods Of 90 eligible patients randomly assigned to three treatment groups, 79 patients completed the study, In group A, patients (n = 25) received artificial teardrops for left and normal saline for right eyes, in group B (n = 29) polyethylene covers for left and normal saline for right eyes, and in group C (n = 25) polyethylene covers for left and artificial teardrops for right eyes. As the patients were comatose, their blinding did not applicable, and a blinded observer evaluated the patients’ eyes based on the Corneal Fluorescein Staining Pattern. The blinded analyzer analyzed collected data by SPSS-16 software at a 95% confidential level. Results The OSDs were observed in 65 (41.14%) out of 158 eyes examined. The artificial teardrop was more effective than the normal saline in group A, polyethylene eye cover was more useful than the normal saline in group B, and polyethylene eye cover was more effective than the artificial teardrop in group C in reducing the incidence of OSD (p< 0.01). Polyethylene eye covers had the most impact on reducing the severity of the OSD compared to the other interventions (p< .001). Conclusions Polyethylene eye covers significantly reduced the incidence and severity of OSD. Using polyethylene cover is suggested as a safe, effective, and accessible eye care intervention for preventing OSD in comatose patients. Trial registration (IRCT201609129014N115), Iranian Registry of Clinical Trials.