Invasive Indo-Pacific lionfish Pterois volitans/miles have become well-established in many western Atlantic marine habitats and regions. However, high densities and low genetic diversity could make their populations susceptible to disease. We examined changes in northern Gulf of Mexico (nGOM) lionfish populations following the emergence of an ulcerative skin disease in August 2017, when estimated disease prevalence was as high as 40%. Ulcerated female lionfish had 9% lower relative condition compared to non-ulcerated females. Changes in lionfish size composition indicated a potential recruitment failure in early summer 2018, when the proportion of new recruits declined by >80%. Remotely operated vehicle surveys during 2016-2018 indicated lionfish population density declined in 2018 by 75% on natural reefs. The strongest declines (77-79%) in lionfish density were on high-density (>25 lionfish per 100 m2) artificial reefs, which declined to similar levels as low-density (<15 lionfish per 100 m2) artificial reefs that had prior lionfish removals. Fisheries-dependent sampling indicated lionfish commercial spearfishing landings, commercial catch per unit effort (CPUE), and lionfish tournament CPUE also declined approximately 50% in 2018. Collectively, these results provide correlative evidence for density-dependent epizootic population control, have implications for managing lionfish and impacted native species, and improve our understanding of biological invasions.