The roots and stems contain anthraquinones, such as emodin and rhein. Emodin "represents a genotoxic risk for humans" while rhein is "a compound devoid of genotoxic capabilities". The anthraquinones have been separated from powdered rhubarb root for purposes in traditional medicine, although long-term consumption of anthraquinones has been associated with acute kidney failure. The rhizomes contain stilbenoid compounds (including rhaponticin), and the flavanol glucosides (+)-catechin-5-O-glucoside and (−)-catechin-7-O-glucoside.

Rhubarb leaves contain poisonous substances, including oxalic acid, a nephrotoxin. The long term consumption of oxalic acid leads to kidney stone formation in humans. Humans have been poisoned after ingesting the leaves, a particular problem during World War I when the leaves were mistakenly recommended as a food source in Britain. The printed information recommending the leaves as a food source was rediscovered during World War 2 and redistributed, leading to further deaths. The toxic rhubarb leaves have been used in flavouring extracts, after the oxalic acid is removed by treatment with precipitated chalk (i.e., calcium carbonate). The LD50 (median lethal dose) for pure oxalic acid in rats is about 375 mg/kg body weight, or about 25 grams for a 65-kilogram (143 lb) human. Other sources give a much higher oral LDLo (lowest published lethal dose) of 600 mg/kg. While the oxalic acid content of rhubarb leaves can vary, a typical value is about 0.5%, meaning a 65 kg adult would need to eat 4 to 8 kg (9 to 18 lbs) to obtain a lethal dose, depending on which lethal dose is assumed. Cooking the leaves with baking soda can make them more poisonous by producing soluble oxalates.