The southern end of I-280 is an interchange in Wood County with exit 71 along the Ohio Turnpike's (I-80/I-90). South of this interchange, the I-280 freeway transitions to State Route 420 (SR 420), a divided highway without access control, that also provides access to a truck stop and other businesses. Continuing north, I-280 runs through farm land and through an interchange with Bahnsen Road, which also provides access to other motorist- and trucking-related businesses. North of the SR 795 interchange, the freeway turns to the northwest. At the Walbridge Road interchange in Walbridge, Ohio, I-280 turns back due north. On either side of the Interstate, the surroundings transition from farms to residential subdivisions. I-280 crosses the rail line used by the Capitol Limited and Lake Shore Limited passenger train routes operated by Amtrak. North of this crossing, the freeway passes into Lucas County.
I-280 turns northwesterly again in the city of Oregon. This area is suburban residential neighborhoods as the freeway approaches the Maumee River. The Interstate crosses the river on the Veterans' Glass City Skyway, an 8,800-foot (2,700 m), cable-stayed bridge. On the opposite bank of the river, I-280 turns northward and passes through an intersection with SR 25. There is one final interchange with I-75 where I-280 terminates.
The highway that would eventually carry I-280, the Detroit-Toledo Expressway, opened as a relocated SR 120 between US 20 and SR 51 by 1955. The highway was extended to Summit Street in Toledo by 1957, and by 1959 was extended into Michigan. By this time, the I-280 designation had been added, but the portion carrying I-280 was not fully converted to Interstate standards until 1990.