The cause of de Quervain syndrome is not established. Critics of this association note of the human mind's tendency to misinterpret activities that are painful as activities that make the problem worse. It's important not to inappropriately reinforce such misconceptions because they are associated with greater discomfort and incapability. Evidence regarding a possible relation with activity and occupation is debated. A systematic review of potential risk factors did not find any evidence of a causal relationship with activity or occupation. One study found that personal and work-related factors were associated with the diagnosis of de Quervain syndrome in a working population; wrist bending and movements associated with the twisting or driving of screws were the most significant of the work-related factors. Proponents of the view that de Quervain syndrome is a repetitive strain injury consider postures where the thumb is held in abduction and extension to be predisposing factors. Workers who perform rapid repetitive activities involving pinching, grasping, pulling or pushing have been considered at increased risk. These movements are associated with many types of repetitive housework such as chopping vegetables, stirring and scrubbing pots, vacuuming, cleaning surfaces, drying dishes, pegging out washing, mending clothes, gardening, harvesting, and weeding. Specific activities that have been postulated as potential risk factors include intensive computer mouse use, trackball use, and typing, as well as some pastimes, including bowling, golf, fly-fishing, piano-playing, sewing, and knitting.

The incidence of diagnosis of the condition is higher in women than in men. The syndrome commonly occurs during and, even more so, after pregnancy. Contributory factors may include hormonal changes, fluid retention and—again, more debatably—increased housework and lifting.

De Quervain syndrome involves noninflammatory thickening of the tendons and the synovial sheaths that the tendons run through. The two tendons concerned are those of the extensor pollicis brevis and abductor pollicis longus muscles. These two muscles run side by side and function to bring the thumb away from the hand (radial abduction). De Quervain tendinopathy affects the tendons of these muscles as they pass from the forearm into the hand via a fibro-osseous tunnel (the first dorsal compartment). Evaluation of histopathological specimens shows a thickening and myxoid degeneration consistent with a chronic degenerative process, as opposed to inflammation or injury. The pathology is identical in de Quervain syndrome cases seen in new mothers.

De Quervain syndrome is diagnosed clinically based on patient history and physical examination, though diagnostic imaging may be used to rule out fracture, arthritis, or other causes. The modified Eichoff maneuver, commonly referred to as the Finkelstein test, is a physical exam maneuver used to diagnose de Quervain syndrome. To perform the test, the examiner grasps and ulnar deviates the hand when the person has their thumb held within their fist. If sharp pain occurs along the distal radius (top of the forearm, about an inch below the wrist), de Quervain syndrome is likely. While a positive Finkelstein test is often considered pathognomonic for de Quervain syndrome, the maneuver can also cause some pain in those with osteoarthritis at the base of the thumb.
Differential diagnoses include:
199 Osteoarthritis of the trapezio-metacarpal joint
299 Intersection syndrome: Pain will be more towards the middle of the back of the forearm and about 2–3 inches below the wrist, usually with associated crepitus.
399 Wartenberg's syndrome: The primary symptom is paresthesia (numbness/tingling).