Background: Globally, more than 450 million people suffer from a mental or behavioral disorder. Psychiatric disorder and its duration, physical illness, family history of mental illness, previous suicidal attempt, unemployment, poor social support, and psychotic symptoms are of the main reasons enabling patients to be suicidal ideates. The purpose of this study is to identify the determinants of suicidal ideation among patients with mental disorders in Mekelle, Ethiopia. Methods: Case-control study design was employed with a total of 221 study subjects (74 cases and 147 controls) in Mekelle, Ethiopia. Suicidal ideation was measured by the Suicidal Behavior Questionnaire-Revised (SBQ-R) scale. Bivariate and multiple logistic regression analyses were performed to determine between the independent and dependent variables. Results: This study revealed that family suicide history (AOR = 6.87, 95% CI [1.138-41.531, P = 0.036), previous attempts history (AOR = 27.457, 95% CI 10.417-72.368, P = 0.0001), family mental illness history (AOR = 3.029, 95% CI 1.088-8.431, P = 0.034), major depressive disorders (AOR = 11.182, 95% CI 2.382-52.501, P = 0.002), and psychiatric comorbid disorders (AOR = 12.245, 95% CI 1.898-78.986, P = 0.008) were significant factors of suicidal ideation. Conclusion: Family mental illness history, family suicide history, previous suicide attempt history, major depressive disorders, and psychiatric comorbid disorders were significant factors of suicidal ideation.