De Quervain disease (DQVD) is one of the most common causes of lateral wrist pain and can lead to significant disability. The current case involves a right-handed, middle-aged, female patient with severe lateral wrist pain due to DQVD. Her pain was not responsive to oral non-steroidal anti-inflammatory drugs, rehabilitation, and repeated corticosteroid injections. Because she refused surgical intervention, we performed ultrasound-guided methotrexate injections (four times). After the injections, dramatic pain relief, functional improvement, and reduction of the thickness of the retinaculum and tendons in the first dorsal extensor compartment of the wrist were noted. This case report highlights the potential usefulness of ultrasound-guided methotrexate injection for recalcitrant DQVD of the wrist.