Not far from the Maryland state line, the road crosses Muddy Run before it comes to the Newark mainline toll plaza.

I-95 widens to eight lanes and reaches a partial cloverleaf interchange with DE 896, which heads north to Newark and the University of Delaware and south to Glasgow.

Following this interchange, the Interstate Highway crosses the Christina River and runs between industrial areas to the north and farm fields to the south, coming to bridges over Norfolk Southern Railway's Delmarva Secondary railroad line and DE 72 without access.

The road heads through more woodland with nearby suburban development as it curves northeast, with the median widening for the Biden Welcome Center service plaza accessible from both directions.

After I-295, I-95/US 202 turns north and comes to a northbound exit and southbound entrance with the southern terminus of I-495, which bypasses the city of Wilmington to the east.

[6][7] Following the I-495 interchange, the median narrows and I-95/US 202 heads northeast through marshland as the six-lane Wilmington Expressway, crossing the Christina River.

The freeway comes to bridges over Norfolk Southern Railway's Shellpot Secondary railroad line and Little Mill Creek as it continues through more wetlands west of the Russell W. Peterson Urban Wildlife Refuge, with Amtrak's Northeast Corridor railroad line running parallel a short distance to the northwest.

[6][7] Past US 202, I-95 leaves Wilmington for the suburban Brandywine Hundred area and continues northeast as a four-lane road, passing southeast of the Rock Manor Golf Club and running along the northwest side of the CSX Transportation line.

The roadway continues through wooded areas to the south of the CSX Transportation tracks, crossing Shellpot Creek and coming to a diamond interchange with DE 3 northwest of the town of Bellefonte.

After this exit, I-95 and the rail line curve to the northeast and continue through woodland with nearby residential areas, passing northwest of Bellevue State Park and crossing Stoney Creek.

The highway crosses Perkins Run before it reaches a northbound exit and southbound entrance with Harvey Road southeast of the villages of Arden, Ardentown, and Ardencroft.

Past this interchange, the freeway curves east away from the CSX Transportation tracks and winds northeast near suburban neighborhoods in Claymont.

[19] In the middle of 2011, reconstruction of the Delaware Turnpike toll plaza was completed in a $32.6-million (equivalent to $43.6 million in 2023[18]) project funded by the American Recovery and Reinvestment Act of 2009, adding high-speed E-ZPass lanes.

[6][7][24] The service plaza offers a Sunoco gas station, electric vehicle charging stations, a convenience store, multiple fast-food restaurants, a visitor center, and retail options including a store called Postcards from Delaware that sells Delaware-related merchandise.

[25][26] When the Delaware Turnpike opened in 1963, a Hot Shoppes restaurant and an Esso service station were located along the road in the median.

[29] In 1983, Hot Shoppes was replaced by Roy Rogers and Bob's Big Boy in order to offer both sit-down dining and fast food.

[42] The same year, recommendations were made for the design and right-of-way acquisition along the planned route of I-95 as well as the construction of several contracts between the Maryland state line and Farnhurst along the Delaware Turnpike, including the interchange with DE 41/DE 141 and between I-95, I-295, and I-495 near the Christina River.

[49] The Delaware Turnpike, along with the connecting Northeast Expressway in Maryland, was dedicated by President John F. Kennedy, Delaware Governor Elbert N. Carvel, and Maryland Governor J. Millard Tawes in a ceremony at the state line on November 14, 1963, in which a ribbon-cutting took place and a replica Mason–Dixon line crownstone was unveiled.

The first motorist to pay a toll on the turnpike was Omero C. Catan, also known as "Mr. First", of Teaneck, New Jersey, who marked this occasion as the 517th first moment he achieved.

As a result, both the Delaware Turnpike and the Northeast Expressway were renamed the John F. Kennedy Memorial Highway in his honor in December 1963.

[4][57] On the one-year anniversary of the dedication of the Delaware Turnpike on November 14, 1964, a memorial service and wreath laying in honor of Kennedy was held at the state line, with Governor Carvel in attendance.

[58] In 1966, I-95 was completed and opened to traffic between the Christina River interchange with I-295 and I-495 and downtown Wilmington, where ramps connected the highway to Maryland and Lancaster avenues.

[76] In May 2007, construction began to widen I-95 between the DE 1/DE 7 and US 202/DE 141 interchanges from eight to ten lanes due to rising traffic levels and increased development.

[78][79] Construction of a new "ring access road" around Christiana Mall began in February 2011[80] and was completed in March 2012, with a newly built bridge over DE 1, just south of the I-95 interchange.

On August 7, 2015, a dedication ceremony to mark the completion of the project was held, with Governor Markell, Senator Tom Carper, and DelDOT Secretary Jennifer Cohan in attendance.

[91] DelDOT completely rebuilt I-95 from the southern end of I-495 to the Brandywine Creek bridge in Wilmington in a $200-million project beginning in February 2021.

[94] On April 6, 2023, a ceremony marking the completion of the project was held, with Governor Carney, Senators Carper and Chris Coons, Representative Lisa Blunt Rochester, Wilmington Mayor Mike Purzycki, and DelDOT Secretary Nicole Majeski in attendance.

[98][99] A groundbreaking ceremony was held on May 1, 2023, with Governor Carney, Senator Carper, Representative Blunt Rochester, and DelDOT Secretary Majeski in attendance.

[98] In March 2021, a group of state lawmakers led by Representative Sherry Dorsey Walker pushed for US Secretary of Transportation Pete Buttigieg, and, by proxy, President Joe Biden, to endorse a plan to add a freeway lid on top of I-95 through Wilmington and construct an urban park on top of the highway, reuniting neighborhoods that were divided when the highway was constructed.

I-295 loops to the north of Trenton, and enters Pennsylvania, heading south (west) and reaching its terminus at I-95 in Bristol Township.