This study assessed the knowledge and management of common psychiatric disorders by general practitioners (GPs) in Karachi, Pakistan. Structured interviews were carried out in 2009 with 360 GPs selected by cluster random sampling. Patients with psychiatric disorders were estimated to be up to 10% of the daily caseload according to 71.8% of doctors. Two-thirds of GPs were unaware of the ICD-10 diagnostic criteria for depression and anxiety disorders. Benzodiazepines were the most recognized category of medication (75.3%) and were the most commonly used medication for all mental health conditions. Fewer GPs were familiar with selective serotonin reuptake inhibitors (35.1%) or tricyclic antidepressants (20.2%). Lack of time and patients’ financial constraints were reported to be barriers to care. Most GPs (69.2%) had not received any recent medical education about mental health problems. Gaps in GPs’ knowledge about the management of mental disorders have implications for the rational use of psychotropic medications in primary care.