Most of its eastern portion is a major freeway linking the greater Manchester area to the Seacoast Region.

At 95.189 miles (153.192 km) in length, NH 101 nearly spans the entire width of southern New Hampshire.

NH 101 continues east through both of these intersections as Marlboro Street, then leaves Keene at the city's southeast corner for the town of Marlborough.

NH 123 leaves southbound on Elm Hill Road, and NH 101 leaves Peterborough at the town's southeastern corner near Miller State Park and Pack Monadnock Mountain, a popular hiking and birdwatching destination.

Joining NH 31 at the northern bank of the Souhegan River, the two routes cross the river to the south bank before NH 31 leaves to the north in the main village of Wilton, while NH 101 continues eastward along the south bank of the Souhegan River along Gibbons Highway into neighboring Milford, where the name changes to Elm Street.

NH 101 joins I-93 north for a short concurrency, along which there is a single interchange at exit 6 with Candia Road and Hanover Street.

Between I-93 and exit 1 in Manchester, as well as between I-95 and Landing Road in Hampton, the NH 101 freeway carries a posted speed limit of 55 miles per hour (89 km/h).

Exit 8 is in Brentwood at North Road, which provides access to the New England Dragway and NH 27.

There is an unnumbered interchange with US 1 (the Hampton Rotary) which provides access to downtown, before the freeway section ends at a traffic light with Landing Road to the east.

NH 101 enters Hampton Beach as a full-access two-lane highway, crosses the marshy estuary system of the Hampton River and its tributaries, then splits into a pair of one-way streets (Highland Avenue eastbound and Church Street westbound) before reaching its eastern terminus at NH 1A (Ocean Boulevard).

Most of the eastern section of NH 101 was originally planned as part of the canceled New England East–West Highway from Albany, New York to Portsmouth.

This road was colloquially known as the Highway of Death for its numerous accidents and large signs at the start of the two-lane freeway segment between exits 5 and 6 in Raymond that displayed the number of fatalities that had occurred.

In 1991, an overpass was constructed over North Road in Brentwood near the Rockingham County Jail Farm for the future routing of NH 101.

According to the state Department of Transportation, the portion from Keene to the Merrimack River was named the Horace Greeley Highway in 1949.

In 1995, the name Jay McDuffee Highway was given to the stretch "from the Epping/Raymond town line to its terminus in Hampton.

NH 101 has long been proposed as a part of the greater East–West Highway, which would provide upgraded freeway connections across the three northern New England states (Maine, New Hampshire and Vermont).

Some early proposals suggested that the route should be part of the Interstate Highway System as I-92, but these were rejected.

More recent proposals have suggested that the entire route could be part of a privately maintained toll road.

The eastern terminus is in the center of Nashua, when it meets New Hampshire Route 111 at the Merrimack River.

Route 101A is quite busy by southern New Hampshire standards, with traffic ranging from 26,000 vehicles per weekday in Nashua to 9,000 in western Milford.

[15] New Hampshire Route 101E is a short stretch of urban road 2.357 miles (3.793 km) in length in Hampton.

Guide signs exist at the eastern terminus at NH 1A, but along the road itself, there is no signage to indicate the route's number.