Zygocotyle, as with other paramphistome trematodes, lives in the posterior intestine or cecum of birds or mammals associated with freshwater habitats. Unmbryonated eggs are released and miracidia hatch after a period of development. These swim to find suitable snail intermediate hosts such as Helisoma spp. After penetrating the snail the miracidium transforms into a mother sporocyst, which produces mother rediae. The mother rediae produce daughter rediae, and these in turn produce cercariae a few months after the initial infection. As with most redial infections in snails, the parasite castrates the snail by consuming its gonad.
Cercariae leave the snail and settle on aquatic vegetation or even shells of snails. There, cystogenous glands in the cercariae secrete a cyst and the parasite becomes a metacercariae. The metacercariae can survive many months, awaiting ingestion by a suitable definitive host so that they can excyst and mature into adults.