Background: Patients’ oral health is impaired in Intensive Care units (ICUs) due to loss of consciousness, open mouth, intubation, and mechanical ventilation. Objectives: The current study aimed to compare the effects of comprehensive and combined programs on oral health in patients under mechanical ventilation. Methods: This single-blind clinical trial with three groups was performed on 90 patients with mechanical ventilation admitted to ICUs of medical centers affiliated to the Zahedan University of Medical Sciences, Iran, in 2020. Patients under mechanical ventilation were randomly divided into three groups, including those receiving a comprehensive program, those receiving a combined program, and controls through permutated blocks. In the two intervention groups, oral care was performed for 5 minutes, three times per day, during the 5 days of the study with a specific method. The control group received routine oral care. The patients’ oral health was measured once before the intervention and then every day until the fifth day of the intervention using the Beck Oral Assessment scale. The data were analyzed using the analysis of variance and chi-square in IBM SPSS Statistics software version 26. Results: The mean oral health score in the three groups was not significantly different before the intervention and on the second day of the study (P > 0.05). However, on the third to fifth days of the study, the oral health score in the two intervention groups showed a significant decrease compared to the control group, indicating an oral health improvement in these groups (P = 0.001). The mean oral health score in the control group increased during the study days. Conclusions: Comprehensive care and combination methods can improve oral health in patients under mechanical ventilation. Nurses are recommended to use regular and codified oral care methods.