Duloxetine, a widely used antidepressant, has not been adequately studied for its long-term adverse effects. This study aims to characterize the long-term safety of duloxetine in the real world. FAERS data from Q1 2004 to Q3 2024 were retrieved, covering adverse event (AEs) reports related to duloxetine. The data were analyzed using algorithms such as ROR, PRR, BCPNN, and MGPS. A total of 4876 AEs were collected, involving 52,205 patients. The top three System Organ Classes (SOCs) were psychiatric disorders, nervous system disorders, and general disorders and administration site conditions. The top three preferred terms based on signal strength were dysphoria (n = 2316, ROR 211.37, PRR 209.43, IC 6.73, EBGM 105.95), telangiectasia congenital (n = 5, ROR 96.55, PRR 96.55, IC 6.06, EBGM 66.69), and affect lability (n = 2520, ROR 85.2, PRR 84.35, IC 5.92, EBGM 60.66). In addition to the AEs already mentioned in the drug label, our study identified unexpected AEs related to congenital, familial and genetic disorders, such as telangiectasia congenital, factor X deficiency, and hemoglobinopathy, emphasizing the safety risks of duloxetine exposure during pregnancy. Furthermore, we observed rare adverse reaction signals, such as phagophobia, lymphocytic oesophagitis, coma blister, and junctional ectopic tachycardia. Notably, female patients reported more cases of drug withdrawal syndrome and opsoclonus myoclonus, while male patients more frequently reported sleep sex, sensory disturbance, semenuria, paedophilia, affect lability, and activation syndrome. Duloxetine may pose an undiscovered risk of AEs related to congenital, familial and genetic disorders. Our findings provide healthcare professionals with evidence to weigh the risks and benefits of duloxetine treatment, particularly for patients of different genders. Further prospective studies are needed to explore rare and unexpected AEs.