Hamilton County

US 27 enters Ohio on the Taylor–Southgate Bridge over the Ohio River as a four-lane highway. After the bridge ends, the highway makes a loop to the east around a parking structure on Pete Rose and Mehring ways, concurrent with US 52. Mehring Way curves towards the west and passes under the Taylor–Southgate Bridge. After the bridge, the street parallels the Ohio River and Smale Riverfront Park on the south side of the road and the Heritage Bank Center and Great American Ball Park on the north side. The street passes under the John A. Roebling Suspension Bridge and then passes to the south of Paycor Stadium.

On the southwest corner of the stadium, US 27 and US 52 turn north onto Central Avenue. Central Avenue passes on the west side of the stadium. The route continues north, passing the west side of the Duke Energy Convention Center, Cathedral Basilica of St. Peter in Chains, and Romanesque Cincinnati City Hall. At Central Avenue and West 3rd Street, US 27 and US 127 begin their concurrency. At Central Avenue and 6th Street, northbound US 27 continues north along Central Avenue whereas the southbound lanes use Central Parkway and Plum Street; both directions of travel merge back together to follow Central Parkway at Ezzard Charles Drive. US 27 and US 127 end their concurrency at Hopple Street as US 127 continues north along Central Parkway and US 27 becomes concurrent with I-75 and then I-74 for a short while.

The route then follows Colerain Avenue, ascending through the Mount Airy Forest from an elevation of 490 to 930 feet (150 to 280 m) in two miles (3.2 km), passing the Cincinnati Water Tanks on North Bend Road. The remaining stretch in Hamilton County is a quite busy multilane highway that passes through the Mount Airy neighborhood, then exits Cincinnati to briefly pass through the corner of Green Township. It then becomes the main commercial thoroughfare through Colerain Township, traveling along a broad ridge that roughly separates the watersheds of the Great Miami River to the west from that of West Fork Mill Creek to the east.

The road then splits at an intersection with Struble Road, with the old alignment of Colerain Avenue branching off, and US 27 following a modern freeway section, passing the "Mount Rumpke" landfill and descending to and crossing the Great Miami River at an elevation of 525 feet (160 m).

Butler County

A herringbone brick intersection of Chestnut Street and Patterson Avenue is at the southeast corner of Oxford at US 27. The highway northwest of Oxford is straight and rural. This final section passes to the west of the Oxford Walmart and within a mile (1.6 km) of the Butler County highpoint before reaching College Corner.^[2]