University Avenue originally ran along a line several blocks north of its current location, forming a route which once connected the Minneapolis campus of the University of Minnesota to Hamline University in Saint Paul (hence the name). When the construction of the Minnesota Transfer Railway yards blocked that route, the street was moved one-half mile to the south on the Saint Paul side, to what was then called Melrose Avenue.). The old University Avenue route was renamed Minnehaha Avenue, which it remains to this day.
Some important neighborhoods the road passes through include Frogtown (officially, the Thomas-Dale neighborhood) and the Midway region, both in Saint Paul. Hubbard Broadcasting Corporation and its flagship stations, KSTP-AM-FM-TV, are located just next to the border of Minneapolis and Saint Paul. In fact, the sidewalk at the KSTP studios is right on the city/county line. This was one of the highest points in the area and made an appropriate site for a radio transmitter. An antenna structure still stands there today, though it is used for microwave links rather than broadcasting (KSTP and most other Twin Cities stations use the Telefarm installation in Shoreview, Minnesota or the nearby KMSP Tower).
In 1890, the first interurban streetcar link between Minneapolis and Saint Paul used University Avenue and Washington Avenue in Minneapolis. History will likely be repeated, since the road, part of the Central Corridor, is considered the next major candidate for a light rail line in the Twin Cities.
University Avenue carries Ramsey County Road 34 in Saint Paul, and Hennepin County Road 36 in Minneapolis to the junction with Interstate 35W. West and north of Central Avenue, University Avenue carries Minnesota State Highway 47 to the junction with U.S. Route 10, after which it carries Anoka County Road 51.