Manganese is an essential trace nutrient in all forms of life. The classes of enzymes that have manganese cofactors are very broad, and include oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases, lectins, and integrins. The reverse transcriptases of many retroviruses (though not lentiviruses such as HIV) contain manganese. The best-known manganese-containing polypeptides may be arginase, the diphtheria toxin, and Mn-containing superoxide dismutase (Mn-SOD).

The human body contains about 12 mg of manganese, which is stored mainly in the bones; in the tissue, it is mostly concentrated in the liver and kidneys. In the human brain, the manganese is bound to manganese metalloproteins, most notably glutamine synthetase in astrocytes. Manganese is also important in photosynthetic oxygen evolution in chloroplasts in plants.

The oxygen-evolving complex (OEC) is a part of photosystem II contained in the thylakoid membranes of chloroplasts; it is responsible for the terminal photooxidation of water during the light reactions of photosynthesis, and has a metalloenzyme core containing four atoms of manganese. For this reason, most broad-spectrum plant fertilizers contain manganese.