Background: Compared with advances in a drug hypersensitivity diagnosis and management, little is known about the mental health status of patients with drug hypersensitivity and the impact of this psychological distress on their quality of life (QoL). Objective: The objectives were to evaluate anxiety, depression, and QoL levels in patients with drug hypersensitivity, assess how some related factors may affect them, and determine the impact of disease on their QoL. Methods: A total of 203 patients with drug hypersensitivity and 80 healthy controls were evaluated with the Beck Anxiety (BAI) and the Depression Inventory (BDI), and the short version of the World Health Organization Quality of Life (WHOQOL-BREF) scale. Results: The mean ± standard deviation (SD) BAI scores of the patients and the controls were 13.46 ± 11.78 and 1.94 ± 1.93, respectively (p < 0.0001). The mean ± SD BDI scores were higher in the patient group (9.23 ± 6.36) than in the control group (2.18 ± 2.02) (p < 0.0001). The patients had significantly increased risk of anxiety versus the controls (48.8% versus 7.5%) (odds ratio [OR] 11.74 [95% confidence {CI}, 4.88-28.20]; p < 0.0001) and depression versus the controls (31.5% versus 6.2%) (OR 6.90 [95% CI, 2.66-17.90]; p = 0.0001). The comparison of patients' BAI and BDI scores showed that those with more severe reactions had higher scores than those with moderate and mild reactions. A negative correlation was found among all WHOQOL-BREF scale domain scores and the BAI and BDI scores. Conclusion: Anxiety and depressive symptoms have a high prevalence in patients with confirmed drug hypersensitivity, which leads to a notable decrease in QoL. Self-administered psychological questionnaires were shown to be useful in the psychological examination and management of patients with drug hypersensitivity. Therefore, we found that psychological support is critical to reducing the negative outcomes of hypersensitivity reactions in patients.