During 16 of 21 consecutive annual breeding seasons, two diseases, Newcastle disease and avian cholera, killed approximately 50% of juvenile Double-crested Cormorants (Phalacrocorax auritus) in a large nesting colony in Canada. From 1994 to 2014, we recorded data annually on disease occurrence, causal pathogens, species and age classes affected, total number of breeding pairs of cormorants on the colony site, and other biological parameters. A mathematical model of pathogen transmission was constructed to assess the potential importance of transmission parameters and to test a hypothesis regarding the potential effect of the observed progressive loss of nest trees and the consequent shift from tree-nesting to ground-nesting behavior. The model indicated that juveniles from ground nests were 14 times more likely to die from epidemic disease (50.14% mortality) than were juveniles from nests in trees (3.57% mortality). Additive disease-related mortality of juvenile cormorants in the observed range of 40–60% would reduce a closed cormorant population over time. There was no directional change in the colony population during the study period, suggesting that immigration had compensated for disease-related mortality. Our results highlight the preeminent influence of environmental factors on pathogen transmission and the value of long-term data sets.