The highway ends at an interchange with Interstate 69 (I-69) north of downtown Fort Wayne after serving the east central and northeast regions of Indiana.

US 27 passes through farm fields and urban areas, and parallel to the Ohio state line.

Realignments and construction projects have expanded the highway to four lanes in Adams and Allen counties.

US 27 enters Indiana heading northwest from Ohio, parallel to CSX Transportation railroad track, in the town of West College Corner.

In West College Corner, the highway passes through the center of town, on a street named Liberty Avenue.

At C Street, the one-way pairs end and the road passes over Norfolk Southern Railway tracks.

The route heads north-northwest from Richmond toward Portland as a two-lane rural highway passing through farmland with a few houses.

The road continues through Fountain City passing the Levi Coffin House, a building on the National Historic Landmark list.

After SR 26, the two routes head through commercial properties, with a few houses, as a two-lane street with a center turn lane.

The concurrency heads north, leaving Portland as a two-lane rural highway and passing through farmland with a few houses.

North of Spy Run Avenue Extended, the one-way pairs end and the road becomes a four-lane highway with a center turn lane, retaining the name Clinton Street.

Lima Road then passes through a mix of residential and commercial properties as a four-lane undivided highway.

At this traffic-light, Lima Road becomes a six-lane divided highway passing through commercial property and heads toward an interchange at I-69.

[7] The NHS is a network of highways that are identified as being most important for the economy, mobility, and defense of the nation.

This measurement is a calculation of the traffic level along a segment of roadway for any average day of the year.

[9] The bridge over I-70 immediately north of Richmond is named the "Officer Seara Burton Memorial Bridge", in honor of Richmond police officer and K-9 handler Burton, who was shot by the subject of a traffic stop on August 10, 2022.

[3] In November 1967, Indiana completed its northern segment of I-69, the last incomplete section being opened between Angola and the Michigan–Indiana state line, supplanting US 27 as a through route.

On March 9, 2007, legislation was introduced in the Indiana House of Representatives to designate US 27 as historic highway.