The creek is named after the Cayuga nation, one of the constituent members of the Iroquois Confederacy.

A sewage treatment facility in the Town of Cheektowaga discharges into Cayuga Creek upstream of Borden Road.

Farther downstream the creek is an important feature in Stiglmeier Park in the Town of Cheektowaga.

After Cayuga Creek flooded the Village of Lancaster twice in the early 1940s,[4] protective dikes were constructed.

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