All parts of the Christmas Rose plant are considered toxic upon consumption or physical contact with sap from damaged plant tissues. This is due to the fact that its organs contain varying levels of different glycosides - which are common plant defense mechanisms against herbivores and microorganisms.

The leaves, stems and flowers of Helleborus niger contain ranunculin and ranuncoside - glycosides whose breakdown yields the toxin protoanemonin when plant cells are damaged. Protoanemonin has an unpleasant taste and can cause irritation of the skin, mucosa and eyes upon contact. If large amounts are ingested, the toxin can cause itching and blistering of the mouth and throat as well as gastroenteritis and hematemesis in both humans and animals.

A key compound in the roots of Helleborus niger is Hellebrin, a bufadienolide which has similar cardiac activity but is less toxic than the cardiac glycosides found in Digitalis and Strophanthus plants. The degradation products of Hellebrin also strengthen heart contractions, but are more toxic than their parent molecule. The aglycon Hellebrigenin has the lowest lethal dose along with stronger cardiac activity than the original glucoside Hellebrin. Though rare, Hellebrin and its derivatives are considered responsible for severe or lethal Christmas Rose poisonings because their interference with the ion channels of the heart can lead to various arrhythmias.