Signed east-west, it runs 24.61 miles (39.61 km) from MD 662 in Wye Mills on the border of Queen Anne's and Talbot counties, southeast to the Delaware state line in Caroline County, where the road continues as Delaware Route 404 (DE 404) to the Five Points intersection near Rehoboth Beach.

By 1946, the route's western terminus was moved to MD 2 north of Annapolis, where it headed east across the Chesapeake Bay on the Sandy Point-Matapeake ferry.

Since MD 404 is the main route for travelers between the Chesapeake Bay Bridge and the Delaware Beaches, the road experienced a high accident rate.

MD 404 begins at an intersection with MD 662 (Old Wye Mills Road) in Wye Mills on the border between Queen Anne's County to the north and Talbot County to the south, heading to the east on Queen Anne's Highway, a two-lane undivided road.

[2] From here, MD 404 continues east through farmland with some residences and wooded areas as a four-lane divided highway, approaching the town of Queen Anne.

[1] It emerges from the woods into agricultural areas, intersecting the western terminus of MD 480 (Ridgely Road) near Hillsboro.

Past that intersection, the route heads through a mix of woods and residences before coming to a superstreet junction with the eastern terminus of MD 404 Alt.

[2] Past this intersection, MD 404 crosses over the Choptank River on the Governor Harry R. Hughes Bridge.

The road turns to the southwest, heading into woods and intersecting the eastern terminus of MD 404 Bus.

MD 313/MD 404 continue as a four-lane divided highway with at-grade intersections that turns south and heads through some commercial areas.

[1][2] The road heads south into farmland, passing east of Martinak State Park.

[1][2] The three routes continue southeast, narrowing into a two-lane undivided road that heads through a mix of woods and farms with some homes.

[2] East of US 50, MD 404 serves as part of the main route connecting the Chesapeake Bay Bridge and the Baltimore–Washington Metropolitan Area to the Delaware Beaches.

[7] By 1933, MD 404 was designated onto a state highway between Matapeake, where the Annapolis–Matapeake ferry across the Chesapeake Bay connected the route to Annapolis in Anne Arundel County, and the Delaware border southeast of Denton.

[8] By 1946, the route's western terminus was moved to MD 2 north of Annapolis in Anne Arundel County, crossing the Chesapeake Bay on the Sandy Point–Matapeake ferry, roughly where the Chesapeake Bay Bridge is now, and continuing west through Skidmore to MD 2.

[19] The primary motive behind the widening was the high accident rate that plagued the two-lane road, brought on by beach traffic.

[23] As part of the American Recovery and Reinvestment Act of 2009 signed into law by President Barack Obama on February 17, 2009, $7.7 million went to widening a portion of MD 404 east of Tuckahoe Creek in Caroline County, creating 221 jobs.

[25][29] Work on widening of the remaining sections of MD 404 between US 50 and Denton was completed on November 20, 2017, with Governor Hogan in attendance for a ribbon-cutting ceremony.

[25][30][31] On May 29, 2011, the Route 404 Memorial Garden, located near Denton, was dedicated, honoring those who were killed in car accidents along MD 404.

The memorial consists of a flagpole surrounded by a circular path with bricks bearing the names of people who died along the route.

passes through woodland, crossing under an abandoned railroad grade owned by the Maryland Department of Transportation before coming to MD 303 (Lewistown Road).

turn south and join again, becoming a four-lane divided highway with the Franklin Street name that runs through woodland.