Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease characterized by vasculitis affecting small blood vessels, primarily in the lungs, skin, and peripheral nervous system. Both rituximab and mepolizumab are recommended for EGPA treatment, but their combined use is uncommon. There have been only a few reported cases of using both drugs together. We present a 46-year-old man with a history of asthma and chronic rhinosinusitis presented with dyspnea, numbness in the feet, and skin lesions. He was diagnosed with ANCA-negative EGPA and treated with corticosteroids and immunosuppressants. Despite initial improvement, he developed respiratory symptoms and osteoporosis. Treatment with mepolizumab helped reduce corticosteroid dosage but was not effective in joint involvement. A combination of mepolizumab and rituximab was then initiated, resulting in significant improvement in joint symptoms and overall disease control. This case demonstrates the challenges of managing EGPA and the need for tailored treatment approaches. The combination of rituximab and mepolizumab proved effective in controlling different disease manifestations. Further studies are needed to evaluate the safety and efficacy of this combination therapy in EGPA.