This study aimed to assess the real-life effectiveness of omalizumab and mepolizumab in patients with severe asthma and chronic spontaneous urticaria (CSU), explicitly examining changes in IgE levels and eosinophil counts during treatment. This retrospective study involved patients with severe asthma or CSU treated with biologic agents, including omalizumab and mepolizumab. The primary outcome measures were serum IgE levels, eosinophil counts, urticaria activity scores (UAS), and asthma control test scores (ACT). We studied 61 patients with severe asthma or chronic urticaria treated with biological agents. Patients with asthma exhibited a significant reduction in the median annual attack rate from 4 to 0 with omalizumab (p<0.001) and from 6 to 1 with mepolizumab (p<0.001). Eosinophil counts, and ACT scores significantly decreased with mepolizumab (p<0.001). Six patients who transitioned from omalizumab to mepolizumab did not experience severe asthma attacks in the first six months following the treatment switch. Patients with CSU showed a significant response to omalizumab (p<0.001). We observed significant improvements in various markers, including total IgE levels, eosinophil counts, UAS, and ACT scores, indicating that these treatments can effectively manage the symptoms of both conditions. These findings underscore the potential benefits of using these treatments as effective therapeutic options.