Avian botulism is a paralytic disease due to the ingestion of botulinum neurotoxins (BoNT) produced by anaerobic, sporigenic bacteria (notably, Clostridium botulinum). Wild waterbirds worldwide are affected with variable recurrence and severity, and organic material decaying in wetland habitats may constitute a suitable substrate for the replication of clostridia strains producing BoNT in conditions of high temperatures and the absence of oxygen. Here, we describe a large outbreak of avian botulism that occurred in the Valle Mandriole protected area of northeastern Italy (VM). After the recovery in late summer of a few duck carcasses that molecularly tested positive for BoNT-producing clostridia, in October 2019, the avian botulism escalation led to a total of 2367 birds being recovered (2158 carcasses and 209 sick birds). Among these, 2365/2367 were waterbirds, with ducks accounting for 91.8% of the total (2173/2367) and green-winged teals representing 93.5% of the ducks. After the quick collection of dead and sick birds (from 4 to 11 October 2019) and the flooding of the VM wetland (from 5 to 12 October 2019), the 2019 botulism emergency apparently ended. Following two water inputs in May and July 2020, only one pooled sample obtained from 16 bird carcasses found that year in VM tested positive for clostridia type C by real-time PCR, whereas, after to the implementation of measures deterring the bird’s presence, new avian botulism cases—due to clostridia type C and C/D, according to molecular and animal-model tests of confirmation—led to the collection of 176 waterbirds (82 carcasses and 94 sick ducks) and 16 waterbirds (9 carcasses and 7 sick ducks) in the summers 2021 and 2022, respectively. In conclusion, the prevention, management, and control of the disease rely on habitat management, the quick and careful collection/removal of animal carcasses, and the regular monitoring and surveillance of live and dead birds.