A portion of the route west of Middletown was realigned in 2017 as a result of the construction of the US 301 toll road.

DE 299 heads east from the Maryland state line on two-lane undivided Warwick Road, passing through farmland.

[5] Shortly after the state line, the route curves north, with US 301 toll road parallel to the east.

The roadway heads south of the Christiana Care Middletown Free-standing Emergency Department before it becomes a divided highway, passing south of a park and ride lot and intersecting the DE 1 toll road at a diamond interchange on the eastern border of Middletown.

Following this interchange, DE 299 becomes undivided again and heads east through a mix of farms and homes into the town of Odessa, where it is called Main Street and curves southeast.

[4][5] DE 299 crosses the Appoquinimink River out of Odessa and heads to the southeast on Old State Road into housing developments.

[5] The route curves south before makes a turn southeast onto Taylors Bridge Road and ends a short distance later at DE 9 in the community of Mathews Corners.

[19] In July 2008, a widening project began on US 301/DE 299 between United Drive and the east end of the concurrency.

[21] On July 15, 2017, DE 299 was realigned near the Maryland border as a result of construction of the US 301 toll road.