In sediment cores spanning ~500 years of history in the Gulf of Trieste, down-core changes in molluscan community structure are characterized by marked shifts in species and functional composition. Between the 16th and 19th century, a strong heavy metal contamination of the sediments, most notably by Hg, together with the effects of natural climatic oscillations (increased sedimentation and organic enrichment) drive community changes. Since the early 20th century up to 2013, the combined impacts of cultural eutrophication, frequent hypoxic events and intensifying bottom trawling replace heavy metal contamination and climatic factors as the main drivers. The pollution-tolerant and opportunistic bivalve Corbula gibba and the scavenging gastropod Nassarius pygmaeus significantly increase in abundance during the 20th century, while species more sensitive to disturbances and hypoxia such as Turritella communis and Kurtiella bidentata become rare or absent. An infaunal life habit and scavenging emerge as the dominant life strategies during the late 20th century. Down-core shifts in the proportional abundances of molluscan species and functional groups represent a sensitive proxy for past ecological changes and reveal a century-long anthropogenic impact as the main driver behind these processes in the northern Adriatic Sea, offering also a unique perspective for other shallow marine ecosystems worldwide.