One tributary forms part of the northern perimeter of Southeastern Louisiana University's main campus, and another tributary flows under the campus in a tunnel starting on the south side of LA 3234 near the Southeastern University Center.

Peter av Hammerdal (Peter Hammond), eponym of Hammond, Louisiana, settled along the Ponchatoula Creek in the early 19th century and used the stream for agricultural and logistical purposes as he supplied wood products to ocean-going vessels in New Orleans.

In modern times the chief use of Ponchatoula Creek is drainage, with much of its channel widened, deepened, and straightened by dredging.

These practical enhancements to Ponchatoula Creek have reduced its scenic quality but greatly improved its efficiency and effectiveness in eliminating flooding.

Ponchatoula Creek forms a habitat for the introduced species Ctenopharyngodon idella, a grass carp fish also known as white amur, which was imported to the US in 1963 from Taiwan and Malaysia, and is often stocked to control vegetation.