Digitalis toxicity is the result of the body accumulating more digitalis than it can tolerate at that time. That can be caused by high levels of digitalis in the body, or it can be caused by "normal" levels but decreased tolerance by the body. Digitalis toxicity can occur from a single exposure, chronic overmedication, or can be precipitated with normal blood levels of digitalis if other risks are present.

Risks include taking digitalis medications such as digoxin or digitoxin, along with medications that interact with digitalis such as quinidine, verapamil, amiodarone, and others.

People with heart failure are commonly given diuretics (medications used to pull excess fluid from the body) along with digoxin. Many diuretics can cause potassium loss. Low levels of potassium in the body increases the risk of digitalis toxicity. Digitalis toxicity can also be precipitated by low levels of magnesium in the body.

Reduced kidney function will cause digitalis to accumulate in the body rather than being excreted normally through urine. Therefore, any disorders that disrupt kidney functioning (including dehydration) make digitalis toxicity more likely.