Antibiotics, in non-resistant strains of the pathogen, can prevent the vegetative state of the bacterium forming. Drug treatment to prevent the American foulbrood spores from successfully germinating and proliferating is possible using oxytetracycline hydrochloride (Terramycin).

Another drug treatment, tylosin tartrate, was approved by the US Food and Drug Administration (FDA) in 2005.

Chemical treatment is sometimes used prophylactically, but this is a source of considerable controversy because certain strains of the bacterium seem to be rapidly developing resistance. In addition, hives that are contaminated with millions of American foulbrood spores have to be prophylactically treated indefinitely. Once the treatment is suspended the American foulbrood spores germinate successfully again leading to a disease outbreak.

Because of the persistence of the spores (which can survive up to 40 years), many State Apiary Inspectors require an AFB diseased hive to be burned completely. A less radical method of containing the spread of disease is burning the frames and comb and thoroughly flame scorching the interior of the hive body, bottom board and covers. Dipping the hive parts in hot paraffin wax or a 3% sodium hypochlorite solution (bleach) also renders the AFB spores innocuous. It is also possible to sterilize an infected hive without damaging either the structure of the hive or the stores of honey and pollen it contains by sufficiently lengthy exposure to an atmosphere of ethylene oxide gas, as in a closed chamber, as hospitals do to sterilize equipment that cannot withstand steam sterilization.

Brigham Young University is currently studying the use of phage therapy to treat American foulbrood.

When cleaning infected cells, bees distribute spores throughout the entire colony. Disease spreads rapidly throughout the hive as the bees, attempting to remove the spore-laden dead larvae, contaminate brood food. Nectar stored in contaminated cells will contain spores and soon the brood chamber becomes filled with contaminated honey. As this honey is moved up into the supers, the entire hive becomes contaminated with spores. When the colony becomes weak from AFB infection, robber bees may enter and take contaminated honey back to their hives thereby spreading the disease to other colonies and apiaries. Beekeepers also may spread disease by moving equipment (frames or supers) from contaminated hives to healthy ones.

American foulbrood spores are extremely resistant to desiccation and can remain viable for more than 40 years in honey and beekeeping equipment. Therefore, honey from an unknown source should never be used as bee feed, and used beekeeping equipment should be assumed contaminated unless known to be otherwise.