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Water fleas infected with guinea worm larvae transmit the disease to humans via contaminated sources of drinking water. The larvae then mature within the body of the host, growing to as long as one meter in the space of 10–14 months. Once an adult female worm is ready to release larvae, it will migrate to areas just beneath the skin, inducing a blister accompanied by itching and pain.
Guinea worms normally inhabit stagnant water such as puddles, ponds, water reservoirs and wells, but tend to be absent from rivers and other running water. Humans are more susceptible to guinea worm infection in arid regions where they drink stagnant water during the rainy season, or from puddles formed in swampland during the dry season when the water level is low.

Normally, no symptoms are observed for about a year from initial infection. Once an adult guinea worm is ready to release larvae, however, it will migrate to just below the skin’s surface, leaving one or more blisters visible on the skin.
At this stage, by cooling the blistered area in cold water, the worm will detect the difference in temperature and emerge from the body to release thousands of larvae. At this point, patients will experience a painful, burning sensation in the area of the blister. Permanent damage can also occur in cases of joint infections, which can cause the joints to lock and deform.
If a worm breaks during removal, the remaining part of the worm will start to degrade inside the body and this can lead to intense inflammation, including cellulitis. Furthermore, if the infection is not properly treated, it can result in other complications such as abscesses, sepsis and tetanus.

Diagnosis is made by the visual inspection of adult worms in blisters on the skin.
Currently, there is no effective drug used for the treatment of guinea worm infection. The only existing treatment is to remove adult worms by applying traction to slowly pull them out from the body once they emerge from beneath the skin. Full extraction of the worm can take from several days to weeks.

Currently, there is no effective vaccine to prevent guinea worm infection, nor will prior infection provide immunity against the disease.
The most effective preventive measure against guinea worm infection is ensuring access to safe drinking water, thereby preventing ingestion of infected water fleas. Concrete measures include using cloth and pipe filters for drinking water and applying an approved larvacide to contaminated drinking-water sources, such as in small ponds or open wells. Another precaution is to ascertain that patients with the disease are kept away from shared sources of drinking water.

The infection risk is high in areas remote from urban centers in Africa where safe drinking water is hard to come by. According to data released by the World Health Organization (WHO) in 2016, infections were reported in only four countries, namely, Chad, Ethiopia, Mali, and South Sudan, with 41% of cases occurring in Chad.

The number of infected people has declined every year since 1986 due to a successful campaign to eliminate infection. According to data released from CDC, 22 people had been infected worldwide in 2015, hinting that complete eradication of the disease worldwide is possible in the near future.

Although the death rate is low, disability is a common outcome of guinea worm disease. Patients often have difficulty moving around because of pain as well as complications from secondary bacterial infections. While disability normally lasts 8.5 weeks on average, it can sometimes be permanent.