The route was originally planned to follow an alignment about midway between US 41 and US 141 (the latter paralleled Lake Michigan at the time) along WIS 57.

However, the moniker generally only applies to the portion of the route in Waukesha and Milwaukee counties;[11][self-published source?]

Exit 72C's northbound off- and on-ramps in downtown Milwaukee pass underneath the county courthouse via tunnels to Kilbourn Avenue.

The urban residential areas thin out north of this point as a mix of farmland and forest begins to dominate.

WIS 32 rejoins the freeway on the northside and the two routes follow the Lake Michigan shoreline northeast into Sheboygan County.

[16] WIS 32 leaves the freeway at Cedar Grove and the Interstate passes Oostburg to the east and Sheboygan to the west.

[17] As of 2007[update], traffic counts in southern Ozaukee County peak at 66,900 vehicles per day—this value generally decreases further north.

[20] I-43 in Manitowoc County has the least traveled portion of the highway with 17,400 vehicles passing south of WIS 147 according to 2005 results.

[21] The Interstate passes Denmark and meets the terminus of WIS 96 one mile (1.6 km) north of the county line.

At this point, the Interstate enters urban residential areas as it approaches Green Bay.

[22] I-43's lowest traffic volume in this county is at the southernmost entry with a 2006 value of 22,100 vehicles per day near Denmark.

The commission, after a study by Wisconsin Turnpike Commission—which was established in 1953—submitted a request in 1963 for a route that connected Milwaukee and Superior by way of Green Bay, Wausau, Hurley, and Ashland which could be completed in increments.

[24] The original plan for the northern part of I-43 was to locate it midway between US 141 and US 41, using most of the current alignment of WIS 57 north of WIS 33 in Saukville;[25] additionally, it was proposed to use the Interstate 57 number,[26] though that was changed due to resistance from Illinois to extend its portion through Chicago.

The last major segment, consisting of 94.4 miles (151.9 km) of roadway, was started in 1972 after the last of these governments, Manitowoc County, pledged its support.

[25] The portion in Milwaukee County extending from the Port Washington Road exit to the Marquette Interchange was completed in 1981 to open the route.

[27] Historically, segregation and related issues meant that this was the only place in Milwaukee where Black citizens could settle; it was later targeted for renewal to rid the city of what its political leadership saw as slums.

Interstate routings for such a connection between Beloit and the Milwaukee metropolitan area were requested by the Wisconsin Department of Transportation (WisDOT) but denied by the Federal Highway Administration (FHWA) in 1973.

Despite the denials, local and state officials continued to seek funding to construct a freeway between these two metropolitan areas.

The next segment, to East Troy, was opened in 1972, the year the Highway 15 Committee had hoped the route would be completed in its entirety.

[32] The Marquette Interchange, which connects I-43 with I-94, and I-794, was completely reconstructed over a four-year span, beginning in October 2004 and ending in September 2008.

[33] A multiple-vehicle collision on the northbound lanes of I-43 involving 52 vehicles, killing three and injuring at least 30 others, occurred on the Tower Drive Bridge at 6:45 am March 12, 1990.

The cause was a wall of fog with extremely limited visibility near the Fox River on an otherwise clear day.

[36] It involved 50 vehicles and was found to have been caused by low visibility due to fog at a point where the freeway comes its closest to paralleling Lake Michigan, 0.7 miles (1.1 km) from shore.

Then-Sheboygan County Sheriff Loni Koenig said of the crash site, "In my 21 years [of law enforcement], this is the most horrific scene I have ever seen, and I'm sure that it is for many of the people there.

[40] I-43 is currently being widened from four to six lanes in total north of Milwaukee from Silver Spring Drive to WIS 60, with the anticipated completion in late 2024.

[41] Rest Area 51 and 52 in Manitowoc County between Cooperstown and Denmark will be replaced with a newer facilities beginning in 2024 and ending in 2025.