The northern segment is entirely concurrent with US 15, beginning at I-180 in Williamsport northward into New York to an interchange with I-86 in Corning.

It begins concurrent with US 220, which continues south from the interchange toward the Maryland state line as a two-lane highway known as the Appalachian Thruway.

North of the turnpike junction, the freeway becomes the Bud Shuster Highway as it heads through a rural portion of Bedford County.

[5] In Hollidaysburg, a borough south of the city, I-99 and US 220 connect to US 22 at exit 28, a large modified trumpet interchange.

At the northern edge of Altoona, PA 764 joins the old alignment of US 220 and parallels I-99 north for three miles (4.8 km) toward Bellwood.

Beaver Stadium, the home of the Penn State Nittany Lions football team, is visible from I-99 at this point.

US 322 continues east through the interchange to follow the Mount Nittany Expressway while I-99 and US 220 split from US 322 and head northeastward toward Pleasant Gap, which I-99 connects to via exit 81 and PA 26.

A four-lane freeway through the Steuben County town of Lindley, I-99 crosses through a rock cut, making a large bend to the north and bypassing the hamlet of Presho.

After CR 5, I-99 turns northeast through the town of Erwin, running to the west of the Indian Hills Golf Club.

After CR 107, I-99 enters a large interchange that utilizes several flyover ramps between I-99, US 15, I-86, and NY 17 (Southern Tier Expressway).

[17] On November 6, 1998, AASHTO formally approved the I-99 designation, which initially extended 51.2 miles (82.4 km) from the Pennsylvania Turnpike in Bedford to PA 350 in Bald Eagle.

[1] In 2002, plans were set in motion to extend I-99 northeast from Bald Eagle to State College via Port Matilda.

[18] Work on the segment ceased one year later[18] as PennDOT attempted to stop the flow of acidic runoff from the site.

[17] The portion of the latter highway north of the PA 26 interchange was originally built in the 1970s as a two-lane freeway connecting Pleasant Gap to I-80.

[citation needed] The piece connecting the PA 26 freeway to the Mount Nittany Expressway was completed in 2002.

On June 27, 2014, New York Governor Andrew Cuomo announced that the interstate-grade US 15 freeway from the Pennsylvania border to I-86 in Corning was officially signed as I-99.

The new interchange will eliminate local access between PA 26 (Jacksonville Road) and I-80, which will be provided by a new exit two miles (3.2 km) to the east.

[23][24] The local access interchange between PA 26 and I-80 was funded in part by a $35-million federal grant, with a total estimated cost of $52 million.

The second phase, the Jacksonville Road (PA 26) project is expected to take two years, cost $6.9 million and completion is now scheduled for the middle of 2026.

[26] During a 2002 taskforce meeting for I-99, it was suggested that I-390, which extends north from I-86 24 miles (39 km) west of the I-86/I-99 junction near Corning and which crosses I-90 and terminates in the greater Rochester metropolitan area, be redesignated as I-99 once the I-80 to I-86 portion of that route is completed.