Lake Erie has experienced multiple anthropogenic-driven changes in the past century, including cultural eutrophication, phosphorus abatement initiatives, and the introduction of invasive species. The benthos of Lake Erie has been studied infrequently over nine decades and can provide not only insights into the impact of environmental changes but can also be used to examine ecosystem recovery through time. We used multivariate analyses to examine temporal changes in community composition and to assess the major drivers of long-term changes in benthos. Eutrophication, water quality improvement, and dreissenid introduction were the major drivers of changes in benthos in the western basin, while hypoxia was a major factor in the central basin, and dreissenid introduction was most important in the eastern basin. Non-dreissenid community composition of the western basin has changed dramatically over 90 years from benthic species indicative of good water quality in the 1930s, with a diverse community dominated by Hexagenia, to one of low diversity dominated by oligochaetes and other pollution-tolerant species in the 1960s, followed by recovery in the early 2000s to a state similar to that reported in 1930. In contrast, the non-dreissenid benthic community of the central basin over 60 years was consistently dominated by low oxygen-tolerant taxa, signifying the persistence of hypoxia, the major community driver in this basin. The eastern basin community also changed dramatically, including the disappearance of Diporeia after the introduction of Dreissena in the 1990s and more recent declines in oligochaetes, amphipods, gastropods, sphaeriid clams, and leeches.