Lake Kutubu is a tropical freshwater lake that is internationally renowned for its biodiversity, 12 endemic species of fish, wetlands, and swamp forests. This study reports on a fish kill and the introduction of exotic species, and it assesses impacts on fish stocks and the artisanal fishery. The fish kill, which began in January 2013 and lasted for 6 months, was characterized by fish pathologies consistent with epizootic ulcerative syndrome. Sleeper gobies and gudgeons (i.e., Mogurnda variegata Nichols, Mogurnda furva Allen & Hoese, Mogurnda kutubuensis Allen & Hoese, and Oxyeleotris fimbriata [Weber]) had more obvious signs of disease than did Hephaestus adamsoni (Trewavas), Melanotaenia lacustris Munro, and Craterocephalus lacustris Trewavas. The event coincided with an inflow of a plume of white particulates from the northeast, where hydrocarbon companies carried out extensive horizontal drilling in 2012–2013. Six months after the event, the main species caught by fishers were Cherax papuanus Holthuis (16%), H. adamsoni (55%) and M. lacustris (28%), which is different from the mix of species found in previous surveys of 1995 and 1997. The recent fish kill, as well as socioeconomic changes, substantially reduced the fish catch and fishing effort. Small-scale fish farmers began raising the genetically improved farmed tilapia strain of tilapia (Oreochromis niloticus Linnaeus) and common carp (Cyprinus carpio Linnaeus) in earthen ponds in 2009 and introduced water hyacinth (Eichhornia crassipes [Mart.] Solms) as a food for these fish. Heavy rains in 2010–2012 released farmed fish into the lake, and in May 2015, fishers report that the fish catch is dominated by tilapia. Improved strategies are required to educate stakeholders, assess fish stocks, and protect biodiversity by reducing anthropogenic impacts.