Aim and background: Flunarizine, a cerebro-selective calcium channel blocker, prescribed worldwide for migraine prophylaxis, has demonstrated efficacy and safety in different migraine types and patient populations, comparable to other first-line antimigraine drugs used for migraines such as propranolol, topiramate, amitriptyline, and valproate. Case description: A 35-year-old female primarily came to the outpatient department for treatment of headache and was started on Flunarizine 10 mg. Her headache significantly reduced but after 8 weeks she reported complaints of low mood, reduced sleep, reduced appetite, loss of interest in work, and crying spells. She was treated with adequate doses of Sertraline but showed no improvement in symptoms. Mental status examination revealed depressed affect, anhedonia, and negative cognition. After ruling out organic causes and medical work-up, drug-induced depression was considered, and flunarizine was stopped, and Sertraline was continued at the same dose. After she reported an improvement in depressive symptoms, the diagnosis was changed to drug-induced depression. Conclusion: Flunarizine may induce depressive symptoms in susceptible patients. Patients receiving long-term flunarizine should be regularly monitored for any signs of depression. If a patient develops symptoms indicative of depression after the initiation of a given agent; another agent should be considered. Clinical significance: As a clinician, we can never be too cautious of the adverse reactions of the prescribed drugs, hence, we should always be vigilant and prepared if the situation ever arrives.