Major metropolitan areas along its route include Miami, Jacksonville, and Savannah in the Southeast; Richmond, Washington, Baltimore, Wilmington–Philadelphia, Newark, and New York City in the Mid-Atlantic; and New Haven, Providence, Boston, and Portland in New England.

[4] The Charleston, Wilmington, and Norfolk–Virginia Beach metropolitan areas, the three major coastal metros bypassed by the highway's inland portion, are connected to I-95 by I-26, I-40, and I-64, respectively.

[7] According to the Corridor Coalition, I-95 serves 110 million people and facilitates 40 percent of the country's gross domestic product.

Before 1987, a notable gap in the highway existed between West Palm Beach and Fort Pierce; I-95 traffic between those cities was diverted to Florida's Turnpike.

In North Carolina, I-95 informally serves as the separation between the state's central Piedmont and eastern Atlantic Plain regions.

Much like its route in South Carolina, I-95 runs through mostly rural areas, avoiding major cities like Raleigh and Durham.

I-95 is the only two-digit interstate highway in Delaware, and it only passes through the Twelve-Mile Circle, the northernmost part of the state.

Northeast of Philadelphia in Bucks County, I-95 joins the Pennsylvania Turnpike near Bristol before entering New Jersey on the Delaware River–Turnpike Toll Bridge.

At the northern end of the turnpike in Fort Lee, I-95 turns southeast and crosses over the Hudson River into New York City via the George Washington Bridge.

I-95 next passes New London and Groton, before the route curves northeast and leaving its close connection to the coast.

North of Boston, I-95 leaves the beltway and heads northward in Peabody, while Route 128 continues east to Cape Ann.

After the first components of the interchange opened on September 22, 2018, I-95 was rerouted onto the Pennsylvania Turnpike, meeting up with where I-95 previously ended at the state line.

[19] In the 21st century, several large projects between Richmond, Virginia, and New Jersey have aimed to decrease congestion along the corridor.

The Springfield Interchange is one of the busiest highway junctions on the East Coast, serving between 400,000 and 500,000 vehicles per day.

With the exception of high-occupancy toll (HOT) lanes on the Capital Beltway (I-495/I-95), this project was completed in July 2007.

This project was completed with the 10 lanes opened on December 13, 2008, greatly reducing the traffic delays on the beltway.

About 30 miles (48 km) north of the Wilson Bridge, and about 20 miles (32 km) south of Baltimore near Laurel, Maryland, construction on a large new interchange began in 2008, was scheduled for completion in late 2011, and opened to traffic on November 9, 2014, which connects I-95 to Maryland Route 200 (MD 200).

In 2006, the Virginia General Assembly passed SJ184, a resolution calling for an interstate compact to build a toll highway between Dover, Delaware, and Charleston, South Carolina, as an alternative to I-95 that would allow long-distance traffic to avoid the Washington metropolitan area.

A long-term multibillion-dollar program to upgrade the entire length of I-95 through Connecticut has been underway since the mid-1990s and is expected to continue through at least 2020.

Work has shifted to reconstructing and widening 12 miles (19 km) of I-95 through New Haven, which includes replacing the Pearl Harbor Memorial Bridge.

Environmental studies for reconstructing and widening 60 miles (97 km) of I-95 from New Haven to the Rhode Island state line are also progressing.

The last segments of I-95 in Florida to remain at only four lanes have now been upgraded, providing motorists with about 500 miles (800 km) of continuous six-lane roadbed.

[23] The proposed route would parallel New Brunswick's four-lane, limited-access Trans-Canada Highway on the US side of the Canadian border.