I-43 begins in Rock County as the eastern leg of a cloverleaf interchange with I-39 and I-90 just east of Beloit. The highway becomes Wisconsin Highway 81 west of the interchange. I-43 passes Clinton to the north at WIS 140 and passes into Walworth County five miles east of WIS 140. I-43 passes north of Darien and crosses US 14 at that point, then junctions with WIS 50 south of Delavan.
In Elkhorn, I-43 junctions with WIS 67, US 12, and WIS 11. I-43 passes through East Troy about ten miles northeast of Elkhorn and junctions with WIS 20 and Wisconsin Highway 120. I-43 then enters Waukesha County at Mukwonago. I-43 crosses WIS 83 at an interchange just southeast of the village. After about eight miles, the highway junctions with WIS 164 just north of Big Bend, and then enters the city of Muskego. I-43 crosses interchanges with South Racine Avenue (CTH Y) and South Moorland Road (CTH O) in Muskego.
Beginning in Muskego, I-43 is known as the Rock Freeway. I 43 then passes into New Berlin and turns east to enter Milwaukee County.
I-43 connects with US 45 south and WIS 100 at South 108th Street. US 45 joins I-43 for one mile, then turns northward onto I-894 west at the Hale Interchange while I-43 follows I-894 east along the Airport Freeway into Greenfield, Wisconsin, crossing interchanges with WIS 24, WIS 36 and WIS 241 along the way. I-43 and I-894 junction with I-94 and US 41, known in Milwaukee as the North-South Freeway, at the Mitchell Interchange. I-43 follows the North-South Freeway (with I-94 and US 41) north into downtown Milwaukee, where it meets I-794 at the Marquette Interchange.
I-43 continues north from the Marquette, while I-94 and US 41 turn westward. I-43 crosses WIS 145 at the McKinley Boulevard and Fond du Lac Avenue interchange. On the way north out of Milwaukee, I-43 passes through Glendale, junctioning with WIS 190 (Capitol Drive) and WIS 57 (Green Bay Ave). WIS 100 and WIS 32 connect at Brown Deer Road and WIS 32 follow I-43 north into Ozaukee County, Wisconsin.
I-43 is joined by WIS 57 three miles north of the county line in Mequon at the junction of Wisconsin Highway 167. WIS 60 terminates in Grafton at the interstate seven miles further north and WIS 32 turns off toward Port Washington one mile north of WIS 60. WIS 33 crosses the route in Saukville. WIS 57 turns north off the freeway, which turns eastward to go around Port Washington to the north. WIS 32 rejoins the freeway on the north side and I-43 and WIS 32 follow the Lake Michigan Shorline northeast into Sheboygan County. WIS 32 leaves the freeway at Cedar Grove and I-43 passes Oostburg to the east and Sheboygan, Wisconsin to the west. I-43 Sheboygan interchanges are at WIS 28, WIS 23, and WIS 42 I-43 enters Manitowoc County afer nine miles from Sheboygan.
I-43 passes Cleveland on the county line. The highway continues to follow the lakeshore to Manitowoc, then bypass the city to the west. I-43 connects with US 151 and WIS 42. WIS 42 north follow I-43 north to the interchange with US 10. WIS 42 leaves to the east along with US 10 east, and US 10 west follow I-43 north to the interchange with WIS 310 where it turns off to the west. I-43 passes Francis Creek and Maribel (at WIS 147) and turns northwestward into Brown County, with a rest stop located just before the county line. The interstate passes Denmark and meets the terminus of WIS 96 one mile north of the county line. I-43 then continues another seven miles to Bellevue where US 141 begins. This interchange provides access to Wisconsin Highway 29, a route I-43 crosses under later.
I-43 junctions with WIS 172 in Allouez then turns northeast to bypass Green Bay to the east, passing under the aforementioned WIS 29. After turning northwestward, I-43 crosses WIS 54 and WIS 57 and the Fox River (Wisconsin). I-43 ends at US 41 and US 141. It is rumored that State Highway 29, from Green Bay to Eau Claire is to be the westward extention of I-43, which will then reconnect with I-94, 100 miles east of Minneapolis.