Under most situations, infection is hard to recognize because the symptoms are mild or even absent. In humans and wild animals, infection is not easily identified. Especially the adult flukes, even if in large number, generally do not cause complications. There is not yet a standard diagnostic test. Therefore, manual diagnosis is done at many levels. Diagnosis basically relies on a combination of postmortem analyses, clinical signs displayed by the animals, and response to drenching. In heavy infection, symptoms are easily observed in sheep and cattle as they become severely anorexic or inefficiently digest food, and become unthrifty. Copious fetid diarrhea is an obvious indication, as the soiling of hind legs and tails with fluid feces are readily noticeable. Even though it not always the case, immature flukes can be identified from the fluid excrement. On rare occasions, eggs can be identified from stools of suspected animals. In developing countries diagnosis and prognosis is often hindered by multiple infections with other trematodes, such as "Fasciola hepatica" and schistosomes, because these flukes are given primary importance due to their pervasive nature.

Amphistomiasis is considered a neglected tropical disease, with no prescription drug for treatment and control. Therefore, management of infestation is based mainly on control of the snail population, which transmit the infective larvae of the flukes. However, there are now drugs shown to be effective including resorantel, oxyclozanide, clorsulon, ivermectin, niclosamide, bithional and levamisole. An in vitro demonstration shows that plumbagin exhibits high efficacy on adult flukes. Since the juvenile flukes are the causative individuals of the disease, effective treatment means control of the immature fluke population. Prophylaxis is therefore based on disruption of the environment (such as proper drainage) where the carrier snails inhabit, or more drastic action of using molluscicides to eradicate the entire population. For treatment of the infection, drugs effective against the immature flukes are recommended for drenching. For this reason oxyclozanide is advocated as the drug of choice. It effectively kills the flukes within a few hours and it effective against the flukes resistant to other drugs. The commercially prescribed dosage is 5 mg/kg body weight or 18.7 mg/kg body weight in two divided dose within 72 hours. Niclosamide is also extensively used in mass drenching of sheep. Successfully treated sheep regain appetite within a week, diarrhoea stops in about three days, and physiological indicators (such as plasma protein and albumin levels) return to normal in a month.